Cell type-targeting nanoparticles in treating central nervous system diseases: Challenges and hopes
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Shanshan Guo
Abstract
Effective and safe pharmacotherapies for central nervous system (CNS) disorders remain a major obstacle to human health worldwide. Nanotechnology offers promise in addressing this challenge by enabling the transport of large molecules across the blood–brain barrier (BBB) and the delivery of multiple drugs. Numerous studies have demonstrated the efficacy of nanodrugs in animal models of various CNS disorders, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, stroke, lysosomal storage disease, and gliomas. Nanoparticles (NPs), tailor-made to enhance drug enrichment locally and promote extended drug release, can prevent neuronal death, decrease neurotoxicity, and inhibit tumor growth. In addition to drug delivery, gene therapy using nanotechnology has emerged as a potentially curative option for neurodegenerative diseases. In this review, we summarize how NPs have successfully crossed the BBB and specifically targeted different cells in various CNS disease models over the past decade. Although nanotechnology holds great promise, several drawbacks and challenges must be addressed before its effective implementation in the treatment of CNS diseases.
1 Introduction
Central nervous system (CNS) diseases comprise a diverse range of traumatic neurological disorders including Alzheimer’s disease (AD) [1], Parkinson’s disease (PD) [2,3], multiple sclerosis (MS) [4], amyotrophic lateral sclerosis (ALS) [5], epilepsy [6], and brain tumors. These conditions are characterized by progressive degeneration of the central or peripheral nervous system, widespread neuronal loss, and inflammation [7,8,9,10]. Among the malignant primary brain tumors, glioblastomas, astrocytomas, and oligodendrogliomas are the most common types of gliomas, representing approximately 20% of all malignant gliomas [11] and characterized by nuclear atypia, increased proliferation activity, and microvessel necrosis, depending on the tumor grade (I–IV) [12]. Despite the FDA’s approval of several new treatments in 2017 and 2022, such as Aducanumab for AD, Epidiolex for Dravet and Lennox-Gastaut syndromes, Inebilizumab for neuromyelitis optica spectrum disorder, Brexanolone for postpartum depression, and Esketamine for treatment-resistant depression (ClinicalTrials.gov), CNS diseases remain challenging to treat, and the currently available treatments mainly relieve symptoms. Additionally, the pharmacological kinetics and targeting mechanisms of approved therapeutics are not well understood [13,14,15].
Nanoparticles (NPs), a type of material that includes particulate substances, are typically defined to be between 1 and 100 nm in size [16]. Due to their ability to be readily taken up by cells, NPs are extensively used for targeting different types of cells in disease therapy [17]. These NPs are either used alone (e.g., exosomes and liposomes) or as part of a high-loaded drug delivery system (e.g., polymeric NPs and solid–lipid NPs) and have been employed as nanomedicines for various human diseases [18]. Recently, nanotechnology has emerged as a promising option for improving the diagnosis and treatment of CNS diseases by facilitating drug transport across the blood–brain barrier (BBB) and targeting specific cell types [19,20,21]. Polymer- and lipid-based NPs have shown great potential for clinical use [22,23,24].
Several studies have explored the progress of nanotechnology in treating CNS diseases from various perspectives, including the types of nanomaterials [25] and CNS diseases [26,27]. Notably, one of the advantages of NPs is their ability to be customized for targeting specific cell types based on their unique requirements. However, there have been few reviews summarizing this topic in the past decade. In this review, we aim to assess the latest advancements and categorize the applications of nanotechnology in the treatment of neurodegenerative and other CNS diseases, including gliomas. To fully leverage the potential of nanomedicine for treating CNS-related diseases, we provide a summary of various types of NPs that target specific cell types, such as neurons, microglia, astrocytes, epithelial cells, and oligodendrocytes, as well as the use of nanotechnology in gene therapy for CNS diseases.
2 Pathways of NPs across the BBB
BBB is a crucial interface of capillary endothelial cells that carefully regulates the transfer of substances between the periphery and the brain, safeguarding the brain from circulating pathogens [28]. BBB is composed of various components, including tight junctions between endothelial cells, pericytes, astrocyte endfeet, microglia, interneurons, basement membranes, and extracellular matrix (ECM) proteins, which collaborate to maintain a semipermeable border (Figure 1). Tight junctions, barrier permeability, and endothelial expression of receptors and transporters help to maintain endothelial cell function [28–30]. Molecules can cross the BBB mainly through receptor-mediated transcytosis and adsorptive-mediated transcytosis facilitated by these receptors and transporters. Astrocytes are glial cells that connect brain capillaries and neurons. The basement membrane encircles the endothelial cells and pericytes and contains various ECM proteins such as heparan sulfate proteoglycans, laminin, and collagen type IV [31,32].
BBB structure and NP transport pathways. TfR1, transferrin receptor 1; IR, insulin receptor; LRP, LDLR-related protein; LfR, lactoferrin receptor; LDLR, low-density lipoprotein receptor; GLUT1, glucose transporter-1; ACST2, amino acid transporter; PLGA/PLA, poly(lactic-co-glycolic acid)/polylactic acid; PBCA, poly(butylcyanoacrylate); CDs, carbon dots.
The highly selective semi-permeable border poses a challenge for the transport of certain drugs to the brain, hindering their effectiveness in treating CNS diseases. In recent years, several new strategies have emerged to overcome this barrier [33]. Invasive approaches, such as intracerebroventricular infusion, have been used, but non-invasive therapies such as oral, peripheral, or intranasal administration are preferred [34]. While most drugs diffuse throughout the brain after crossing the BBB, they often do not accumulate at a specific site [35]. Apomorphine (AMP), a drug employed to treat PD and other movement disorders [36], is believed to encounter blockage or degradation before reaching the intended target site [37]. In contrast, NPs can deliver drugs to a specific site, protecting their functional groups and preventing premature drug release [7,8,33,38]. Organic NPs, such as liposomes and polymeric NPs, are biocompatible and biodegradable, and can target cell-specific ligands, crossing the BBB mainly through receptor-mediated transcytosis or carrier-mediated transport. In contrast, inorganic NPs use transcellular or paracellular transport to cross the BBB (Figure 1) [39,40]. NPs can also be modified with specific ligands to leverage transporters in the BBB, such as glucose transporter 1 [41] and amino acid transporter [42]. The favorable properties of organic NPs make them an effective and non-invasive drug delivery tool for the treatment of CNS diseases [43]. Furthermore, NPs can be used wirelessly to stimulate nerve cells in the deep brain [44,45]. Overall, the emergence of NPs as a drug delivery tool offers a promising solution to the challenge of transporting drugs across the BBB to treat CNS diseases effectively.
Effective drug delivery to the brain remains challenging due to several factors. Although researchers have identified potential targets for modifying the surface of NPs, the protein corona can mask functional ligands and prevent NPs from crossing the BBB and being cleared [46,47]. Ligand-modified NPs may also become trapped within brain capillary endothelial cells due to the high binding affinity of ligands with receptors, reducing the amount of NPs that cross the BBB [48,49], and increasing their clearance by microglia before reaching the target site [50]. Additionally, the efflux mechanisms of drug metabolites and waste products remain unknown [51–53].
3 Nano-strategies targeting different cell types
Although some drugs can cross the BBB owing to their favorable properties or the use of nano-delivery systems, their effectiveness in treating CNS diseases has been unsatisfactory. In light of the varying roles played by different cell types and regions in the progression of these diseases, recent therapeutic strategies have focused on the development of nanomedicines that target specific cell populations in the CNS. In this article, we provide a brief overview of the cells that are of interest in the design of nanodrugs based on their physiological functions (Figure 2).
Specific ligands for cell-type targeting in NP designation. Ab: antibody; Apo-E: apolipoprotein E; B2R: bradykinin receptor B2; CD11b: integrin alpha-M; CR: complement receptor; CD204: cluster of differentiation 204; CD36: cluster of differentiation 36; ECM: extracellular matrix; g7: a glycosylated 7-amino acid-long peptide; RGD: arginyl-glycyl-aspartic acid; RVG: rabies viral glycoprotein; LRP1: LDL receptor related protein 1; SSTR2: somatostatin receptor 2; Tet1: Tet methylcytosine dioxygenase 1; Tf: transferrin; TLR: toll-like receptor; TrkA: tyrosine kinase A; Ts1: tityusserrulatus (a neurotoxin binding voltage-gated sodium channel).
3.1 Neurons
Functional neurons make up only approximately 10% of the cells in the brain, but they are critical therapeutic targets as they are often impaired in many types of brain pathology. Manipulating the growth and activity of neurons is a promising strategy for treating patients with neurodegenerative diseases or nerve damage resulting from trauma. However, targeting disease-related neurons in a clinical setting is challenging due to their non-phagocytic nature and diversity of neuron types [54].
One approach involves leveraging the intrinsic ability of vehicles to interact with neurons. For example, apolipoprotein E (ApoE) is the primary lipoprotein produced by astrocytes in the brain, and it delivers essential lipids to neurons by binding to the cell membrane. Wang et al. conjugated ApoE to a lysosomal enzyme, α-l-iduronidase, to treat lysosomal storage disease (LSD), and they observed that this complex accumulated in neurons and astrocytes [55]. After long-term treatment, 2–3% of normal brain α-l-iduronidase activities were recovered from the mouse models of mucopolysaccharidosis type I [55]. Under inflammatory conditions, monocytes and macrophages secrete exosomes that can cross the BBB [56]. In addition to negative targeting approaches, NPs can be designed to recognize neurons based on potential ligands such as dopamine [57], Tet1 peptide (binds to gangliosides and sphingophospholipids, specifically expressed in neuronal cells) [58–60], tyrosine kinase A [61], lactoferrin, rabies virus glycoprotein (RVG)-29 peptide [62], Ts1 (a neurotoxin binding voltage-gated sodium channel) [63,64], antisauvagine-30 [65], and arginyl-glycyl-aspartic acid peptide [66,67]. Pathological neurons also provide targets, such as the hydroxyl-terminated generation of four polyamidoamine (PAMAM) dendrimers, which accumulate specifically in injured neurons [68].
3.2 Microglia
Microglia are long-surviving, self-renewing innate immune cells in the CNS that play crucial roles in maintaining a healthy microenvironment that enables adequate neuronal activity by clearing debris and invading pathogens. However, overactivated microglia can exacerbate the progression of most CNS diseases by inducing neurotoxicity and inflammation [69–71]. Recently, NPs have been used to specifically downregulate the immune state via gene editing [72–74]. In addition, compounds that target microglial inflammasomes, such as rosiglitazone [75], MCC950 [76], Sargramostim, and Fingolimod [77], can be delivered using nanocarriers to prevent dopaminergic (DA) neuron loss in the SNC in PD. Thus, NPs offer promising potential for re-normalizing microglia in CNS disorders [78].
Microglia are crucial players in the pathogenesis of several CNS diseases including MS [79]. Current treatments for MS are not curative [80–82]; therefore, nanomedicines targeting microglia have emerged as promising therapeutic options [83]. For example, novel biomimetic Cu2−x Se-PVP-Qe NPs have been coated with neural cell membranes to specifically target microglia and modulate their polarization into an anti-inflammatory M2-like phenotype to relieve neuroinflammation [84]. The 2.8 ± 0.2 nm sized Cu2−x Se-PVP-Qe NPs specifically recognized microglial molecule-1 and α4β1 integrin, enhanced the expression of the M2-like biomarker CD206, and restored the dopamine level in the cerebrospinal fluid (CSF) and tyrosine hydroxylase (TH) back to the normal level [84]. Curcumin-loaded mPEG-b-PLA NPs effectively reduced oxidative stress in endothelial cells and inhibited M1-microglial activation in a mouse model of ischemia/reperfusion injury [85]. Similarly, dihydrolipoic acid-containing gold NPs changed microglia from polarized M1 microglia to M2 microglia in an ex vivo brain slice stroke model [86]. Despite their phagocytic nature, specific targeting ligands (TLR2, TLR4, CR3, CR4, CD36, and CD204) have also been modified to enhance microglial recognition [87].
Although microglial targeting holds immense potential for treating CNS-related diseases, several challenges still need to be addressed.
Owing to its phagocytic and digestive nature, how can lysosomal degradation be avoided to ensure drug utilization?
How can pathological or activated microglia be targeted?
Like a double-edged sword, NPs themselves (like metal-containing NPs) are also one of the potential factors that cause an immune response in the CNS [88].
How can a delivery system targeting other cell types be designed to prevent microglial clearance?
3.3 Astrocytes
Astrocytes are specialized glial cells that provide support to neurons and outnumber neurons over fivefold [89]. They are also critical components of the BBB, contributing to tight junctions between specialized endothelial cells by secreting soluble factors and enveloping the junctions with their endfeet [90,91]. Notably, astrogliosis is a reliable and sensitive marker of the diseased CNS [92], making targeting astrocytes an increasingly attractive approach for treating diseases.
Several strategies have been employed to specifically target astrocytes using nanomedicine. For example, apolipoprotein E was modified on the surface of lipid NPs for delivering mRNA via intracranial injection [93]. Chitosan NPs containing small interfering RNA (siRNA) were also modified with transferrin receptor (TfR) and bradykinin B2 receptor (B2R) antibodies to specifically downregulate gene expression in astrocytes [94]. In another study, Vismara et al. grafted primary amines to the surface of rolipram-containing nanogel (NG)-based delivery systems, which specifically modulated A1 astrocytes to downregulate their inflammatory toxic effects in a mouse model of spinal cord injury [95]. By co-culturing with primary neurons, astrocytes, and microglia from the spinal cords of mouse embryos, they found that NG accumulated in astrocytes much more than in microglia following exposure to the cells for 24 h [95]. However, it should be noted that astrocytes do not always protect neurons. In a study by Hawkins et al., maternal exposure to cobalt and chromium NPs resulted in neuronal DNA damage via astrocytes [96]. In summary, nanomedicine holds great promise in normalizing pathological astrocytes in CNS diseases.
In addition to their supportive functions for neurons, astrocytes also play a crucial role in protecting against metal-related toxicity by absorbing metal NPs such as iron, copper, and silver NPs [97,98]. However, exposure to titanium dioxide NPs has been found to cause mitochondrial injury in primary astrocytes [99]. Conversely, certain types of NPs, such as selenium NPs, have been shown to exert a protective effect on primary cortical neurons and astrocytes during oxygen-glucose deprivation and reoxygenation [100]. Furthermore, in various CNS disorders, astrocytes have been targeted to reduce neuronal inflammation and oxidative stress [101].
3.4 The basal membrane: endothelial cells and pericytes
The vascular basement membrane, predominantly composed of brain capillary endothelial cells, plays a crucial role in maintaining BBB integrity [102]. Pericytes embedded in the basement membrane and astrocyte endfeet provide support to the endothelial cells. Under neuropathological conditions, changes in the molecular composition of the endothelial cell–cell junctions can result in the loss of BBB integrity [103].
The endothelium represents the first obstacle to be overcome by NPs attempting to cross the BBB via active pathways. To improve drug delivery efficiency and minimize off-target effects in other organs, NPs can be designed to target brain endothelial cells by exploiting the differential endocytic rates of brain and peripheral endothelium [104]. However, a significant proportion of NPs taken up by endothelial cells are degraded by lysosomes, leading to both a failure in the escape of these cells and cytotoxicity in the endothelium [105]. Rassu et al. demonstrated that chitosan-coated or -uncoated solid lipid NPs are a viable option for the penetration of siRNA across epithelial cells following nasal administration [106]. Khan et al. modified NPs with an MMP-1-sensitive fusion peptide, HER2-targeting K, and low-density lipoprotein receptor-related protein-1 (LRP1)-targeting angiopep-2, and demonstrated their ability to escape the BBB [107]. Liposomes have been shown to remain intact inside lysosomes, enabling their escape from endothelial cells [108]. Saturation of endolysosomes by large amounts of Tf-modified liposomes can facilitate the passage of remaining NPs through the BBB and their subsequent release into the brain parenchyma [109]. Gold NPs injected into the mouse CSF have been observed to accumulate in the basement membrane on the outer side of cortical arteries, highlighting the basement membrane as a potential pathway for NPs to exit the brain [110]. However, other studies have demonstrated that Au NPs can impair tight junctions and increase BBB permeability in mice [111].
The toxicity of NPs to endothelial cells is another crucial concern that must be addressed. Studies have shown that concentrated non-toxic engineered carbon and iron oxide NP can cause oxidative/nitrosative stress, energy metabolism imbalance, and mitochondrial dysfunction in endothelial cells [112,113]. Additionally, silica NPs were found to induce oxidative stress through the JNK/P53 and NF-κB pathways in endothelial cells [114]. Although the uptake of NPs by endothelial cells is inevitable, they activate the cells [115]. The effects on endothelial cells are determined by factors such as size, shape, surface ligands, and charge [116].
Pericytes, which are highly expressed in small blood vessels, play a crucial role in maintaining the integrity of the BBB, increasing trans-endothelial electrical resistance, inhibiting immune cell trafficking, and regulating the transcytosis of endothelial cells [117]. However, pericytes are also vulnerable to damage [118]. Another study reported a reduction in the number of astrocytes and degeneration of pericytes in a diabetic mouse model [119,120]. The depletion of pericytes (e.g., PDGFRbC+/−) can lead to impaired BBB functionality [117]. Although an approach to activate or inhibit pericyte function has enormous potential to help treat cellular pathologies in CNS diseases [121], it is difficult to target pericytes using NPs due to the lack of specific markers. In contrast, targeting the basal membrane is comparatively easier, but crossing the BBB to increase drug delivery efficiency using NPs without damaging the BBB remains a challenge.
3.5 Oligodendrocytes and oligodendrocyte precursor cells
Oligodendrocytes are highly vulnerable cells in the CNS that undergo a precise program of proliferation, migration, differentiation, and myelination [122]. Once damaged, they are difficult to repair. This is particularly evident in age-related demyelinating diseases such as MS, where remyelination is challenging [123]. Rittchen et al. developed poly(lactic-co-glycolic acid)-based NPs, modified with NG-2 chondroitin sulfate proteoglycan antibody, to deliver leukemia inhibitory factor to oligodendrocyte precursor cells, successfully increasing myelin repair in a model of focal CNS demyelination [124]. In this study, oligodendrocyte-targeting NPs were able to increase both the number of myelinated axons and the thickness of myelin per axon [124]. Similarly, chitosan NPs were shown to deliver LIN-GO-1-directed siRNA to the brain, promoting central remyelination in a rat model of demyelination [125]. Retinoic acid-containing NFL-lipid NPs (RA–NFL–LNC) were reported to promote the differentiation of primary neural stem cells toward oligodendrocytes [126]. This was demonstrated by the results showing that the Oligo2+ cell numbers in the brain sections from the mice treated with RA–NFL–LNC after lysolecithin-induced focal lesions were more than three times that of the mice treated with vehicle, indicating oligodendrocyte repopulation by RA–NFL–LNC [126]. Additionally, a type of extracellular vesicle containing MiR-219a-5p showed better efficacy in OPC differentiation and experimental autoimmune encephalomyelitis (EAE) cure than liposomes and polymeric NPs [127]. Li et al. designed DNA NPs that could activate transit transcription, promoting the differentiation of human pluripotent stem cells toward oligodendrocytes [128]. However, due to the vulnerability of oligodendrocytes, researchers must exercise caution in ensuring NPs’ safety. Jenkins et al. demonstrated that “stealth” PEG-modified NPs could evade major brain cells, including oligodendrocytes [129]. Sruthi et al. also demonstrated that functionalized super-paramagnetic iron oxide NPs had no toxicological or morphological effect on oligodendrocytes, with no oxidative stress or inflammatory response to the brain [130]. In summary, the design of NPs for targeting oligodendrocytes and oligodendrocyte precursor cells is still a long way because of their vulnerability and potential adverse effects.
3.6 Brain microenvironment
In addition to the BBB, the brain microenvironment poses another challenge for drug delivery to the CNS [131]. It comprises a porous and electrostatically charged brain ECM, soluble molecules, and other components that can influence drug diffusion into the brain. Furthermore, the surface properties of NPs can affect cellular tropism in the brain. Stealth NPs were found not to be taken up by any of the cell types, remaining in the extracellular space in the brain, unless they were functionalized with bio-adhesive end-groups [132].
The brain microenvironment is also affected during brain injury, including the compromised BBB, reactive astrocytes, activated microglia, and necrotic/degenerating neurons [133]. A reactive oxygen species (ROS)-responsive polymeric micelle system has been reported to remodel microglia and correct the inflammatory status in the early stages of AD [134]. In another study, Shi et al. developed a novel biomimetic decoy-integrated NP for managing the over-activated brain microenvironment in ischemic stroke mouse models. The multifunctional NPs featured a shell composed of CXCR4-expressed mesenchymal stem cells membrane, promoting their accumulation in cerebral ischemic lesions and disrupting the infiltration of neutrophils and macrophages. Additionally, the NPs absorbed and neutralized CXCL12, preventing the polarization of microglia. The cargos carried by the NPs, such as A151, effectively induced the polarization of microglia towards the M2 phenotype. This innovative approach demonstrates promising potential for precise immune modulation in the context of ischemic stroke, offering a targeted strategy for therapeutic intervention [135]. The tumor microenvironment in the brain is similar to that in the periphery, consisting of neighboring cells, molecules, and vascular and lymphatic networks. Wang et al. used Pep-1 and CREKA peptides to modify paclitaxel-containing NPs to enhance their ability to cross the BBB, penetrate into the parenchymal cell, and accumulate in the fibrin–fibronectin complex-rich microenvironment in glioblastoma [136]. Although researchers have begun to evaluate the brain microenvironment, there are still few biomarkers or proven nanomedicines available to target this complex system.
The fate of NPs after crossing the BBB and being taken up by neuronal cells is a crucial area of study that has been largely neglected. Recent evidence suggests that NPs may be transported between different cells within the brain, independent of their surface properties, following uptake by neurons or glial cells [137]. Such cell-to-cell transport could have significant implications for the distribution and accumulation of NPs within the brain, as well as their potential toxicity and therapeutic efficacy. Further research is needed to fully understand the mechanisms of cell-to-cell transport and their impact on NP-based drug delivery to the CNS.
4 Nanotechnology targeting CNS diseases
Neurodegenerative diseases are characterized by progressive dysfunction and loss of neurons in the CNS [3,138], including PD, AD, MS, and ALS. Chronic immune activation is another common characteristic of neurodegenerative diseases, in which reactive microglial cells play a major role [139–144]. Thus, cell type-specific targeting is crucial for treating CNS diseases, and NPs can be designed to achieve this goal [38,145,146] (as shown in Figure 3). Various types of NPs have been studied to improve drug delivery to the neurons. Table 1 summarizes the different types of NPs applied to neurodegenerative diseases based on their target cell types.
Cell-type NPs for treating neurodegenerative diseases.
Neurons and microglia targeting NPs for treating CNS diseases
| Targeting cell | Targeting markers | NP type | Surface modification | Delivered compounds | BBB transport pathway | Administration | Encephalic region | Disease | Bio-safety | Animal | Year | Ref |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Neuron or microglia | — | Ag NPs | — | — | — | Nose inhalation | Cerebrum and cerebellum | Neurotoxicity and immunotoxicity | C57BL/6 mice | 2010 | [249] | |
| Neuron | — | Ferulic acid (FA) and glycol chitosan | — | Chitosan and FA | Through the ruptured blood capillaries and interrupted brain-spinal cord barriers | Intravenously | Gray matter and white matter | Spinal cord contusion injury | Neuroprotective | Long-Evans rats | 2014 | [250] |
| Neuron | Nicotinic acetylcholine receptor | mPEG-PLGA | RVG peptide | DFO | Possibly via nAchR-mediated | Intravenously | Substantia nigra and striatum | PD | Biocompatible of RNP-DFO in brain and other organs | C57BL/6 mice | 2018 | [62) |
| — | — | Fe3O4-NPs, 30 nm | — | — | — | Intranasally instilled | Hippocampus | Potential oxidative damage in the striata | SD rats | 2013 | [251) | |
| Ischemic neuron | Glutamate receptor | A dextran polymer core modified with ROS-responsive boronic ester and a red blood cell membrane shell | Stroke homing peptide | NR2B9C | Stroke homing peptide-mediated transcytosis | Intravenous injection | Ischemic brain region | Middle cerebral artery occlusion | BBB | Rats | 2018 | [225] |
| Neuron | Transferrin receptor | Magnetic NPs | Transferrin, FITC | — | Receptor-mediated transcytosis | Perfusion into the internal carotid artery (ICA) | Corpus striatum, hippocampus, thalamus, substantia nigra, mesencephalon, and cerebellum | — | — | Wistar rats | 2013 | [252] |
| Neuron | — | Au NPs, 5 nm | Positively charged | — | Olfactory pathway | Aerosol, locust antenna exposure | Whole brain | — | No significant alterations in their spontaneous and odor- evoked spiking properties | Locust | 2017 | [253] |
| Neuron | — | RVG-TP peptide NPs | RVG and transportation peptide | CASP3 siRNA | Via vicinity of areas with a compromised BBB | Tail intravenous injection | Injured hemisphere | Traumatic brain injuries | — | C57BL/6 mice | 2016 | [254] |
| Retinal neuron | — | P3HT NPs | Thiophene | — | — | Subretinal injection | Entire subretinal space | Retinitis pigmentosa, and age-related macular degeneration | — | Rat | 2020 | [255] |
| Dopamine neuron | — | Electromagnetized Au NPs | — | — | — | Implant | Striatum | PD | Mice | 2017 | [256] | |
| Blood-borne inflammatory monocytes | — | Carboxylated PLG NPs, 500 nm | — | — | — | Intravenous infusion | Injury site | Spinal cord injury | No toxicity found | C57BL/6 mice | 2017 | [257] |
| Microglia | — | PLGA-PEG NPs | CD47 extracellular domain, BBB-penetrating peptide CRTIGPSVC (CRT) | Nec-1s | Transferrin receptor-mediated transcytosis | Intravenous injection | Whole brain | AD | — | C57B6/J mice | 2020 | [258] |
| Neuron and microglia | Amyloid | Superparamagnetic iron oxide NPs | Amyloid Ab | — | — | Intravenous injection | Amyloid plaques | AD | — | Mice | 2017 | [259] |
| Microglia | Ionized calcium binding adaptor molecule 1 (Iba1) | FePt-NPs | Iba1 Ab | — | — | Intravenous injection | Amyloid plaques | AD | — | Mice | 2017 | [260] |
| Microglia | — | Silica NPs | Gadolinium or tetramethyl rhodamine iso-thiocyanate | — | — | Intravenous injection | Tumor | Glioma | — | Nude mice | 2011 | [260] |
| Microglia | Scavenger receptor class A | Iron oxide NPs | Sulfated dextran | — | — | Intravenous injection | Inflammation region | Cerebral inflammation | Biocompatible to microglia | BALB/c mice | 2018 | [261] |
| Microglia | CX3CR1 | PLGA NPs | CX3CR1 siRNA | — | Intrathecal injection | Injection sites | Spinal nerve ligation | — | Rat | 2020 | [262] | |
| Microglia | Iba1 | Superparamagnetic iron–platinum (FePt) NPs | Iba1 Ab | — | — | Intravenous injection | Infarcted region in the ischemic hemisphere | Cerebral ischemia | — | Rat | 2020 | [74] |
| Microglia | — | Curdlan NPs | — | NF-κB siRNA or p65 siRNA | Via vicinity of areas with acompromised BBB | Intravenous injection | Stroke lesion | Stroke | — | Balb/c mice | 2020 | [263] |
4.1 PD: DA neurons
PD is a common multisystem neurodegenerative disorder characterized by progressive degeneration of DA neurons in the substantia nigra and striatum [2,147]. The severity of motor and non-motor symptoms is directly correlated with the extent of DA neuron loss [148]. In addition to DA loss, PD is characterized by the accumulation of α-synuclein and Lewy bodies in the neurons [148,149]. Although levodopa preparations, dopamine agonists, and monoamine oxidase-B inhibitors are the primary medical therapies [150,151], more effective treatments are needed to improve PD therapy.
Nanotechnology has emerged as a promising strategy for delivering dopamine agonists or α-synuclein inhibitors to neurons or the microenvironment in the CNS of animal models of PD. For instance, one approach involves implanting an intracranial nano-enabled scaffold device that carries DA and releases it consistently in the parenchyma of the frontal lobe [152]. Another approach uses polyethyleneimine polymeric NPs (PEG-NPs) to carry RA to DA neurons by inducing the expression of Nurr1 and Pitx3 in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-induced PD mice following intrastriatal stereotaxic injection [153]. PEG-NPs have also been reported to enhance the penetration of curcumin across the BBB and prolong its retention time in the cerebral cortex and hippocampus [154]. The curcumin-loaded NPs were demonstrated to prolong t 1/2 of curcumin in the cerebral cortex to 19.9 ± 2.63 min and in the hippocampus to 16.7 ± 2.56 min [154]. Additionally, PEG-NPs have been used to protect AMP from oxidation before accumulation in the brain via intranasal delivery [155]. Interestingly, acidic PLGA-NPs have been found to rescue compromised lysosomes and protect DA neurons via intraperitoneal injection in healthy mice [156]. Similarly, chitosan NPs encapsulating pramipexole and lactoferrin NPs loaded with rotigotine have successfully preserved DA levels and increased functioning and activity in PD animal models following intranasal administration [157,158]. Polysorbate (PS) 80 cerasome NPs encapsulating curcumin have shown similar abilities to recover DA neurons in a PD mouse model following intravenous administration [159]. Furthermore, RVG 29-modified PLGA NPs (RVG-NPs) have successfully delivered an iron chelator, deferrioxamine (DFO), to the stratium and substantia nigra in PD mice and rescued DA neuronal damage [62]. RVG-NPs were demonstrated to target NeuN+ neurons in the stratum and TH+ neurons in the substantia nigra, decrease their cellular iron levels by delivering DFO, and rescue TH levels in MPTP mice [62].
However, some NPs have been developed to target microglia, with the aim of downregulating inflammation and treating PD [160]. Overall, nanotechnology provides promising tools for more effective and precise treatment of PD.
4.2 AD: neurons and microglia
AD is the most prevalent neurodegenerative disease among the elderly and is characterized by progressive cognitive and memory decline, functional impairment, and neuropsychiatric symptoms [161–163]. Key pathological features of AD include the accumulation of extracellular amyloid plaques and intraneuronal hyperphosphorylated tau proteins [164,165]. In recent years, nanotechnology has been used to eliminate these pathological hallmarks in AD animal models.
Most treatments, including nanotechnology, focus on eliminating amyloid beta (Aβ) [1,15]. Intracerebral injection of hydrogen-containing NPs has been shown to restore learning properties, synaptic function, and neuronal death [166]. These NPs prolonged the release of hydrogen, reducing Aβ aggregation and oxidative stress by inducing the antioxidative pathway and improving mitochondrial dysfunction in AD mice [166]. To develop milder treatments, PLGA NPs encapsulating vitamin D-binding protein (DBP) were intravenously administered to 5XFAD transgenic AD mice, resulting in decreased Aβ plaque formation and AD pathology [167]. Chitosan-l-valine NPs were also used to deliver the poorly-permeable drug saxagliptin throughout the brain by intraperitoneal delivery [168]. Recently, a novel nanocomposite was developed to combine Aβ aggregates on the surface to form nanoclusters following intravenous tail injection in AD mice. Aβ nanoclusters are then phagocytosed and digested by microglia, thereby mitigating Aβ-induced neurotoxicity [154]. In another study, anti-Aβ1-42-functionalized NPs were intravenously injected into AD mice to clear brain Aβ, leading to significant correction of memory defects. However, the poor penetration of anti-Aβ NPs into the brain suggests that the treatment mainly clears peripheral Aβ [169]. In brief, nanodrugs target the Aβ pathway mainly by reducing the continuous synthesis and clearing the abnormal aggregation of Aβ in animal models of AD.
Recent studies have also aimed to target the tau pathway, which is closely associated with the symptoms of AD. One promising approach involves designing a methylene blue-loaded NP (CeNC/IONC/MSN-T807), which was injected stereotactically and demonstrated the ability to either bind to hyperphosphorylated tau or inhibit other tau-associated pathways [170]. The nanocomposite was shown to target Tau+ neurons, downregulate p396-Tau and p205-Tau, decrease the Tau filaments in TEM images, and rescue other cell populations, such as Iba-1+ microglia and GFAP+ astrocytes in the brains of AD mice [170]. Another study in 2019 reported on a novel mesoporous nano-selenium (MSe) multifunctional delivery system (MSe-Res/Fc-β-CD/Bor) which had borneol (Bor) conjugated to its surface to enable it to cross the BBB, and β-cyclodextrinnanovalves (Fc-β-CD) were added as a “lock” to control the opening of specific sites by redox to release resveratrol [171]. Intravenous administration of MSe-Res/Fc-β-CD/Bor was found to protect nerve cells and improve memory by reducing oxidative stress, inhibiting Aβ aggregation, and suppressing tau hyperphosphorylation [171].
Noninvasive strategies, such as oral administration, are preferred over invasive approaches when treating patients. Memantine hydrochloride (MEM) encapsulated in PLGA-PEG-NPs has been reported to increase its efficacy and drug release profile while decreasing its required dose through oral administration in transgenic AD mice [172]. The MEM-PLGA-PEG NPs can cross the BBB, reach the hippocampus, and significantly improve functionality compared to free MEM and control treatments. Histochemical staining has shown that animals treated with NPs exhibit less Aβ plaque formation and decreased inflammation [172]. In addition, oral administration of either pioglitazone (PGZ) or PGZ-loaded PLGA-PEG NPs can decrease memory impairment and Aβ deposition in APP/PS1 transgenic mice. Treatment with PGZ-NPs results in less Aβ deposition than treatment with free PGZ [173]. Furthermore, nanotechnology has been applied to the early diagnosis of AD [174,175].
A sensitive peptide nanonetwork biosensor was designed to detect peripheral platelet-secreted Aβ, and showed promising results for early disease detection [175]. In conclusion, there is increasing focus on the use of nanotechnology to treat AD. However, it remains challenging to precisely target the critical region and distinguish between soluble and insoluble Aβ.
4.3 MS: oligodendrocytes, astrocytes, phagocytic cells, and T-cells
MS is a chronic neurodegenerative disorder characterized by demyelinated lesions and widespread inflammatory processes within the CNS [176]. In patients with MS, widespread lymphocyte infiltration, microglial, and macrophage activation induce demyelination, synaptic, axonal, and neuronal loss [177–179]. Nanotechnology has provided a novel therapeutic approach for MS by manipulating the polarization states of macrophages [179].
Nanoformulations have been used to enhance the efficacy of existing drugs and to reduce their adverse effects. In EAE animal models, which are widely used to study MS [13,180], liposomes loaded with various immunodominant peptides of myelin basic protein have shown efficacy in treating EAE rats, possibly due to the mannosylation of liposomes and the encapsulation of peptides [181]. Another study demonstrated that encapsulation of dimethyl fumarate (DMF) in solid lipid-based NPs (SLNs) improved its effect on disease modification in cuprizone-induced demyelinated mice following oral administration [182]. Furthermore, histological staining of the stomach showed that mice treated with cuprizone and free DMF exhibited mucosal damage, whereas DMF-SL-NP-treated mice did not show any malignancies [182]. In addition, curcumin-encapsulated chitosan-alginate-sodium tripolyphosphate NPs effectively reduced immune cell infiltration, astrocytic and microglial activation, and demyelination in mice with LPC-induced demyelination following intraperitoneal injection [183]. NPs carrying glucocorticoids (GCs), which are commonly used to treat acute relapses in MS, have also been shown to be effective in treating EAE in mice. In one study, dexamethasone was encapsulated in inorganic-organic hybrid NPs and injected intraperitoneally into EAE mice [184]. BMP-NPs are mainly endocytosed by phagocytic cells rather than by T cells, thus decreasing the side effects of GCs [184].
Several recent studies have reported tolerogenic effects in murine relapse-remitting EAE models through the delivery of antigens using polymeric PLG-NPs, which is an interesting finding [185–187]. For example, PLG-NPs have been utilized to deliver proteolipid peptides (PLP139–151) and ovalbumin to antigen-presenting cells, resulting in immune tolerance observed in various signaling pathways, including transcription factor activity, cytokine secretion, and T-cell activation [185–187]. These studies suggest that nano-carrier systems in MS disease models may act on a wide variety of cells, including oligodendrocytes, astrocytes, phagocytes, and T-cells. Although reducing the inflammatory response is the main target in treating MS, improving tolerogenic effects may be a promising strategy for future research.
4.4 ALS: microglia
ALS is a devastating neurodegenerative disease that targets upper and lower motor neurons, leading to severe muscle atrophy and weakness [188,189]. In addition, inflammatory processes within the CNS are believed to contribute to disease pathology, as evidenced by the presence of reactive microglia in neurodegenerative areas of the ALS brain [188,190]. However, the number of nanodrugs used to treat ALS is limited. One of the few nanodrugs used in ALS treatment is cerium-oxide NPs (CeNPs), an antioxidant that was orally administered to SOD1G93A mice, which has been shown to extend the survival time from 22 to 33 days [191]. The beneficial effects observed in the CeNP-treated group can be attributed to a decrease in reactive oxygen and nitrogen species [191].
4.5 Stroke: neuron and microglia
Stroke is a devastating global cerebrovascular disease characterized by interruption of blood supply, resulting in neurological dysfunction [192–194]. Under ischemic stroke conditions, decreased BBB integrity results in increased paracellular permeability, which directly contributes to cerebral vasogenic edema, hemorrhagic transformation, and increased mortality [195]. Although most patients survive after the first onset, only a few are cured during long-term rehabilitation. The rapid development of nanotechnology in other areas of modern medicine has ignited widespread interest in its potential in the field of stroke treatment [196–198]. The identification of stroke biomarkers and the microenvironment also provides possibilities for designing stimuli-responsive nanodrugs [199,200].
Recent advances in nanotechnology for stroke treatment include global [201–204] or targeted [205–209] contrast enhancement of imaging, nanosensors [210–213], theranostics [214–216], improved drug delivery [217–224], and tunable drug release [225,226]. Different types of nanomaterials, such as perfluorocarbon NPs, iron oxide NPs, and gold NPs, have been developed for the diagnosis and treatment of strokes [196–198]. Among these, polymeric and lipidic NPs are the most commonly used vehicles for compounds and have been applied in the co-delivery of chemotherapeutic agents, clot-busting drugs, and neuroprotective drugs [227]. For example, the effective delivery of complement component C3 (C3)-targeted siRNA via cationic lipid-assisted PEG-PLA NPs successfully traversed the BBB. This delivery system significantly suppressed C3 expression in microglia, thereby preventing neuronal apoptosis and reducing the volume of the ischemic zone [228]. Their immunofluorescence staining results unequivocally indicated the specific uptake of C3 siRNA-loaded NPs by Iba-1+ microglia in the ischemic penumbra. Furthermore, these NPs downregulated C3 levels to nearly half of those in the control group [228]. The combination of stem cells and nano-capsules is also promising for treating stroke. Alginate hydrogel microcapsules were used to carry EGF-loaded NPs, which were then trapped in palmitic acid-CLEVSRKNC peptide-coated mesenchymal stem cells to target the stroke region [229]. This smart multiscale system showed better strength, stability, specificity, and retention time than hydrogel microcapsules. Local implantation of the multiscale system facilitates tissue regeneration and effectively restores blood perfusion within 4 weeks without evident side effects [229]. Although a wide repertoire of nanocarriers has been demonstrated to be effective in animal models, it is still challenging to choose the right carrier, identify the appropriate route of administration, and meet clinical needs.
4.6 LSDs: neuron
LSDs are rare inherited metabolic disorders that result in defects in lysosome function [230–233]. These disorders occur due to deficiencies in enzymes required for lipid, glycoprotein, or mucopolysaccharide metabolism, which results in the accumulation of large undigested or partially digested molecules [231–233]. Therapeutic options for LSDs currently available include enzyme replacement therapy or chaperone therapy [234]. NPs have contributed significantly to the delivery of enzymes or chaperones across the BBB and protect them before reaching the target site.
For the treatment of mucopolysaccharidosis type II (MPSII), a type of LSD, brain-targeted polymeric NPs loaded with iduronate 2-sulfatase (IDS) have been shown to successfully remove the deposited glycosaminoglycans [235]. IDS enzyme-delivering NPs effectively removed GVG in fibroblasts from MPSII patients and MPSII mice [235]. Similarly, RVG peptide (RVG29-Cyspeptide)-modified chitosan NPs were used to deliver β-galactosidase (β-Gal) to nude mice, and the accumulation of active β-Gal in the brain indicates the potential of RVG-chitosan NPs in treating β-Gal-related diseases such as Hurler’s syndrome and Krabbe disease [236–238]. Different types of NPs have been tested to absorb or conjugate arylsulfatase A (ASA) on the surface and were intravenously injected into the ASA −/− MLD mouse model. Unfortunately, no significant change was observed compared to the free ASA-administered group [239]. This failure was attributed to the interference of glycoprotein-ASA during receptor-mediated transcytosis of NPs crossing the BBB [240].
4.7 Primary brain tumors: glial cells
Primary brain tumors are a relatively uncommon form of cancer but are the most common and fatal solid tumors among children [241]. In adults, gliomas and CNS lymphomas are the most frequent primary brain tumors [242]. Gliomas can originate from various cell types, including neural stem cells and progenitor cells, but their underlying causes are still largely unknown.
Drug nanoformulations offer several advantages for treating gliomas, including improved efficiency across the BBB, deeper tumor penetration, and decreased adverse effects. For instance, cisplatin-loaded PAA-PEG NPs improved the long-term survivors from none to 80% of F98-tumor-bearing rats when administered locally [243]. Non-invasive therapy using camptothecin-encapsulated PLGA-NPs administered via tail vein injection significantly reduced tumor growth in GL261-bearing mice [244]. To achieve better brain penetration, An-PEG-DOX-Au NPs, loaded with DOX and modified with angiopep-2, were developed, resulting in increased median survival time to 2.89-fold longer than that of saline in a Kunming glioma mouse model after intraperitoneal injection [245]. The ability of these NPs to cross the BBB via the LRP1 receptor and specifically target glioma cells is the most likely cause of their improved anti-glioma effect [245]. Similarly, transferrin-modified PEG NPs encapsulating temozomolide (TMZ) and a bromo-domain inhibitor (JQ1) increased the median survival time of U87MG and GL261 tumor-bearing mice when administered intravenously [146]. Inhibition of tumor growth was also demonstrated in U87 glioma-bearing mice treated with TMZ and vincristine loaded in solid lipid NPs (SLNs) and nanostructured lipid carriers (NLCs), and tumor growth inhibition was greater in mice treated with VT-NLCs than in those treated with VT-SLNs and T-NLCs [149]. The receptor-mediated transcytosis pathway is the mechanism by which most of the functionalized NPs mentioned above cross the BBB.
The cell-mediated transport of NPs provides another option for penetrating brain tumors. In one study, scientists loaded catalase into polyion complex micelles (nanozymes) [246] and found that bone marrow-derived macrophages delivering this nanozyme protected the nigrostriatum against MPTP intoxication. Further evidence has shown that nanozymes can be transported by bone marrow-derived macrophages to contiguous neural cells, including brain microvascular endothelial cells, neurons, and astrocytes [246]. Neutrophils, the most abundant type of immune cell known to penetrate inflamed brain tumors [247,248], have also been shown to be excellent carriers of nanodrugs [248]. For example, neutrophils carrying liposomes containing paclitaxel can penetrate the brain and suppress glioma recurrence in mice whose tumors have been surgically resected [248]. Cancer therapeutic molecule-delivering NPs have also been shown to penetrate brain tumors and efficiently inhibit tumor growth compared with free drugs.
In summary, poor penetration into the tumor site and rapid resistance to a single drug remain limiting factors in brain tumor therapy, and the development of nanocarriers is needed to address these issues. Owing to the critical role of the CNS, specific targeting is more urgent in treating brain tumors than in other types of tumors.
5 Gene tools by nanotechnology targeting neurodegenerative diseases
Gene therapy holds great promise for the treatment of neurodegenerative and CNS diseases by modulating the expression of specific genes and changing the phenotype [264]. Although several genetic medicines have been introduced, their high costs and safety concerns continue to be significant considerations for the wider community [265]. The latest advancements in gene delivery have led to the emergence of virus-based vectors, particularly the adeno-associated virus, which has gained regulatory approval. However, clinical trials have revealed certain limitations of virus-based gene delivery systems, including cost, packaging capacity, toxicity, and immunogenicity.
NPs provide an alternative to viral vectors for delivering genetic material to the nervous system. Notably, lipid-based NPs have shown remarkable potential for gene delivery over the past 5 years [266,267]. However, gene therapy using nanotechnology remains challenging due to the need for a large number of cells to counteract or reverse the malfunction, escape immune responses, and survive for longer periods [268].
Silencing genes through siRNAs, CRISPR, or enhancing them through antisense oligonucleotides (ASOs) are common strategies for gene modulation. However, the invasive administration of these molecules through injection or direct infusion into the brain carries certain risks, making this strategy impractical and unacceptable. Therefore, combining gene therapy with nanotechnology is a promising approach for the treatment of CNS diseases [268]. Recent experiments have used NPs to deliver genes to the brain. Table 2 lists the specifications of these NPs, the genetic products they carry, their cell targets, and the disease and animal models used in the in vivo experiments.
Evaluation of NPs used for gene therapy in recent in vivo experiments
| NPs | Surface modification | Gene tool and target gene | Disease model | Cell target | Animal model | Published | Year |
|---|---|---|---|---|---|---|---|
| Polymer (PLA) | PEG | siRNA; C3 | Cerebral ischemia | Microglia | C57BL/6 mice | 2018 | [228] |
| Polymer (PDMAEMA) | PEG | siRNA; BACE1 | AD | Neurons | APP/PS1 double transgenic mice | 2018 | [275] |
| Exosome | RVG | siRNA; α-synuclein | PD | Neurons | C57BL/6 (transgenic) mice | 2014 | [272] |
| Solid–lipid (T7-LPC) | Transferrin protein (T7) | siRNA; EGFR | Glioma | — | nu/nu mice | 2016 | [273] |
| Cationic nano-emulsion | siRNA; anti-TNFα | Neuro-inflammation | Microglia | Sprague–Dawley rats | 2016 | [270] | |
| Lipid NP | Calcium phosphate-coated | ASO; SOD1 | ALS | Motor neurons | Danio rerio | 2017 | [275] |
| Lipid vector (SNALP) | Chlorotoxin | AMO; anti-miR-21 | Glioblastoma | — | C57BL/6 mice | 2015 | [276] |
| Liposome | Transferrin protein | Plasmid DNA; β-galactosidase | Neurons | C57BL/6 mice | 2018 | [279] | |
| Polyethylene glycol substituted lysine 30-mers | Plasmid DNA; hGDNF | PD | — | Sprague–Dawley rats | 2019 | [280] | |
| GNP | NGF | Plasmid DNA; SNCA | PD | DA neurons | C57BL/6 mice | 2018 | [274] |
| Polymer (DGL) | RVG | Plasmid shRNA; BACE1-AS | AD | Neurons | C57BL/6 APP/PS1 double transgenic mice | 2016 | [281] |
| Poly(β-l-malic acid)-trileucine polymer | Six peptide vectors | Vectors | AD and tumor mouse models | — | C57BL/6 J mouse model with AD, or brain tumors | [282] |
Abbreviations: BACE1, B-site amyloid precursor protein cleaving enzyme 1; BACE1-AS, B-site amyloid precursor protein cleaving enzyme 1 antisense; C3, complement component 3; DGL, dendrigraft poly-L-lysine; EGFR, epidermal growth factor receptor; GFP, green fluorescent protein; GNP, gold NPs; hGDNF, human glial-cell line-derived neurotrophic factor; IVT-mRNA, in vitro transcribed mRNA; NGF, nerve growth factor; PEG, polyethylene glycol; RVG, rabies-virus glycoprotein; shRNA, short hairpin RNA; SNALP, stable nucleic acid lipid NPs; SNCA, α-synuclein; SOD1, superoxide dismutase 1; TNFα, tumor necrosis factor-α; T7-LPC, T7 peptide-liposome-protamine-chondroitin sulfate.
5.1 siRNA
SiRNAs are commonly delivered using nanotechnology techniques, such as intranasally administered manganese chitosan-matrix NPs encapsulating anti-eGFP siRNAs or RFP dsDNAs that successfully transfected neurons along the rostral-caudal axis of the brain [269]. Exosomes are also well-verified nano-tools for siRNA delivery [269].
Recently, functional siRNA carriers have been reported, such as anti-tumor necrosis factor (TNF) siRNA delivered by a cationic nano-emulsion, which downregulates TNF expression via intranasal administration [270]. Nanocarriers for intravenous or intraperitoneal injections have also been optimized to cross the BBB and accumulate at specific sites or cells in different disease models. For instance, β-site amyloid precursor protein cleaving enzyme 1 (BACE1) siRNAs containing NPs were modified with the CGN peptide for BBB penetration and the Tet1 peptide for neuron-specific binding, enabling them to escape from the lysosomes of neurons and induce gene silencing in an AD mouse model [271]. This resulted in hippocampal neurogenesis, fewer amyloid plaques, and lower phosphorylated tau levels [271]. RVG-conjugated exosomes encapsulating α-synuclein siRNA were shown to decrease α-synuclein levels in the striatum and mid-brain following peripheral injections [272]. Using a transgenic mouse model of PD, α-synuclein siRNA-RVG-NPs were found to decrease α-synuclein aggregation throughout the brain [272]. Transferrin-modified core–shell (T7-LPC) NPs were designed to deliver epidermal growth factor receptor (EGFR) siRNA to the glioma site, resulting in prolonged survival in mice compared to control treatment [273]. In this study, live imaging of mice bearing glioma showed that T7-LPC NPs delivered siRNA deeper into the brain than the NPs without transferrin modification, as well as prolonged retention time in the brain tumor. In addition, the T7-LPC NPs were demonstrated to downregulate EGFR level to almost half of the control group in glioma [273]. Polymeric PLA-PEGylated NPs loaded with siRNA were shown to be transported across the BBB and taken up by microglia in the ischemic penumbra of cerebral ischemia and reperfusion injury mice, and delivery of C3 siRNA to microglia reduced microglial neurotoxicity by downregulating C3 expression [274]. In conclusion, stable and traditional nanotools, such as polymeric NPs, chitosan-matrix NPs, and lipid NPs, can effectively deliver siRNA across the BBB after modification without causing significant side effects. Furthermore, these siRNA delivery tools have been applied to various CNS disease models.
5.2 Oligonucleotides
Gene therapy for CNS diseases has seen a surge in the use of ASOs in recent years, leading to FDA approval of an SMA therapy in 2016. However, the use of nanotechnology to administer ASOs has been limited. Studies have reported the successful delivery of ASOs against SOD1 using solid–lipid phosphate calcium lipid NPs, which diffuse throughout the brain and spinal cord of zebrafish [275]. Additionally, stable nucleic acid lipid particles (SNALP) have been used to deliver MiR-21 anti-mRNA oligonucleotides (AMOs) to glioma cells using chlorotoxin-induced glioma-specific targeting, resulting in effective therapy [276]. In fact, NPs delivering AMOs inside tumor cells have been shown to downregulate MiR-21 mRNA expression and repress tumor activity [276]. Recently, a G-Quadruplex-forming aptamer was reported to exhibit resistance to nuclease in the serum and demonstrated its efficacy in enhancing motor neuronal function in a Drosophila melanogaster model expressing the mutated form of human huntingtin [277,278].
5.3 Plasmid DNAs
Multiple studies have demonstrated the potential of functional NPs for delivering plasmid DNAs to the CNS [274,279–281]. For instance, transferrin and penetratin-modified liposomes (PenTf-liposomes) have been designed for better penetration into brain cells [279]. Intravenous injection of PenTf-liposomes encapsulating pGFP DNAs demonstrated their accumulation in the brain and transfection in neurons [279]. In another study, a glial cell line-derived neurotrophic factor (GDNF) plasmid delivered by poly-ethylene glycol-substituted lysine was administered intranasally to rats, resulting in global and long-term expression of GDNF in the brain [280]. Additionally, NPs offer the advantage of combination therapies. RVG-coated dendrigraft poly-lysine NPs were designed to encapsulate both therapeutic genes and peptides to target two key hallmarks of AD pathology [281]. BACE1 short hairpin RNA (shRNA) plasmid and a peptide inhibiting tau-related fibril formation were loaded together into RVG NPs. These multifunctional RVG NPs successfully reduced neurofibrillary tangles and rescued memory loss in AD mice [93]. However, plasmid delivery still faces challenges such as nanosize and low transfection efficacy.
In conclusion, nanotechnology-based gene editing holds tremendous potential for the treatment of CNS diseases. However, their biosafety must be thoroughly evaluated before conducting clinical trials. For instance, although rare, neurological side effects of the SARS-CoV-2 mRNA vaccine have been reported [283]. Additionally, an adeno-associated virus vector, which is an effective gene delivery tool, caused the death of two patients who received a high dose of AT132 during investigational therapy [284]. Therefore, it is crucial to carefully assess the safety and potential risks of these gene-editing tools to minimize any potential adverse effects in patients.
6 Clinical translations of NPs in treating CNS diseases
Although significant progress has been made in the treatment of CNS disorders in animal models, relatively few clinical trials have been conducted. However, some promising results have been reported [285,286]. For example, a novel gadolinium-based NP (AGuIX) combined with radiotherapy was shown to be safe and feasible in a phase I clinical trial [287]. Exosomes have also shown promise as nanocarriers in clinical trials due to their ability to be taken up by immature myeloid cells [288]. They have been used to deliver therapeutics across the BBB to treat neuralgia and refractory depression (NCT04202783 and NCT04202770). Additionally, autologous plasma-derived exosomes have been used to treat chronic multisystem autoimmune disorders (NCT02565264) [288], an early clinical trial, a spherical nucleic acid was reported to cross the BBB and kill tumor cells in humans [289].
7 Conclusions and future directions
7.1 Outcomes and potential targets
To date, various NPs have been designed to exploit transporter proteins, channels, and receptors to cross the BBB. Diagnostic imaging often employs gold, quantum dots, and magnetic iron NPs. Liposomes, exosomes, dendrimers, and polymeric NPs are commonly used as drug carriers due to their biocompatibility. Nano-gels [290] and nano-emulsions [291] have emerged as ideal candidates for CNS drug storage and delivery. Self-assembled peptides and therapeutic compounds have also demonstrated potential for less invasive applications [292,293]. Although most NPs are administered intravascularly, intranasal administration through the olfactory system is another option for NP transport to the brain [294].
In the treatment of CNS diseases, therapeutic targets have received significant attention. For instance, NPs have been developed in animal models of PD that target DA neurons to modify disease pathology by enhancing the development of these neurons. Besides targeting dopamine or oxidative stress, cellular pathways such as α-synuclein, glucocerebrosidase, and leucine-rich repeat kinase in neurons have also been explored as potential targets [151]. In addition, autoimmunity, neuroinflammation [295], and chaperone-mediated autophagy [296] observed in PD offer other possibilities for synergistic therapy using nanotechnology.
Recent advances in nanocarriers have improved their efficacy in the treatment of AD by delivering compounds that target Aβ deposits and hyperphosphorylated tau proteins. As our understanding of AD pathogenesis deepens, the ubiquitin proteasomal system [297], mitochondria [298], and microglia [299] have been found to play indispensable roles in AD progression. Notably, curcumin has been demonstrated to be effective in treating both PD [149] and AD [300] by exerting a neuro-protective action through multiple pathways, including AD-related enzymes, Aβ, tau-related proteins, mitochondria, and metal chelation [300]. Despite the promising results of the described nanocarriers, there is currently no perfect type of NPs (mainly polymeric but composed of different materials) or widely used route of administration for AD therapy. In the case of MS treatment, most NPs are designed to target inflammation and are taken up by a wide range of cells, including oligodendrocytes, astrocytes, phagocytic cells, and T cells. However, there has been limited research on NPs targeting ALS.
NPs have demonstrated their effectiveness in delivering drugs into the CNS, modifying disease pathology, and delivering genes to various cell types. The multifunctionality of drugs in nano-formulation, including improved efficiency across the BBB, co-delivery of drugs, and specific targeting, highlights their potential in treating CNS diseases. Nevertheless, while NPs can be modified and tailored to target different cell types, it remains challenging to accurately target them in different encephalic regions (Figure 4).
CNS-targeting NP design criteria.
7.2 Safety concerns and challenges
Although the use of NPs has demonstrated effectiveness in carrying drugs across the BBB in CNS diseases, their development is still in its early stages, and there are concerns regarding their safety. These concerns are primarily related to biocompatibility, biodegradability, and potential immune responses to administered NPs. Most studies have been conducted using animal disease models, and although some studies have included histopathological analysis and evaluation of inflammatory cytokines, further long-term evaluation is necessary. Despite the demonstrated efficacy of nanodrugs for treating CNS diseases, the exact fate of NPs after crossing the BBB remains unclear, leading to unforeseen safety concerns.
Free drugs can cause toxicity in organs and cells owing to their rapid spread throughout the body. NPs can overcome this problem by increasing targeting specificity, which has been demonstrated in many studies to decrease the toxicity and side effects of free drugs [301]. However, the adverse effects of NPs must also be evaluated. To study the safety of NPs more extensively, Knudsen et al. measured several parameters, such as histopathology, gene toxicity, and gene expression, after administering liposomes and micelles to mice. They observed that micelle treatment increased cytokine (IL-6 and CCL2) gene expression in the liver, as well as oxidative stress response gene (HMOX1) and DNA repair enzyme gene (OGG1). Histopathological assays showed no toxicological effects of NPs on various tissues, such as the liver and lungs [301]. However, other studies have reported cytotoxicity of certain types of NPs, such as PAMAM dendrimers [302], silica NPs [283,284], metal-containing NPs [88,305], and gold NPs [306]. Various reviews have highlighted that cytotoxicity may be influenced by the NP dose, NP coating, size, shape, and distribution [302–304,307]. Despite the potential of NPs to reduce drug toxicity, nanomaterials themselves may pose new safety concerns, requiring comprehensive and long-term monitoring.
Other concerns regarding NPs in CNS therapy include their pharmacokinetics, particularly their ability to penetrate the BBB. Although NPs have been shown to effectively deliver drugs into the CNS, their efficiency in crossing the BBB still needs to be optimized. However, the process of transferring waste products from the brain to the periphery remains unclear. To accurately assess the efficacy of NP penetration, it is important to study their behavior in the same disease model for which they are intended for therapy, rather than in healthy animals. In certain diseases such as stroke, where the BBB is compromised, there may be more opportunities for NPs to cross the barrier, but repairing the BBB is also a crucial consideration.
Another issue that needs to be addressed is the protein corona, which is formed by biomolecules that bind to the surface of NPs during circulation in biological fluids [308,309]. Disturbed by the steric hindrance from the protein corona, the functionalized NPs were unable to cross the BBB [47], target specific cell types, and distribute among the organs unpredictably [310–312]. Recent studies have shown that the protein corona perturbs proteostasis and remodels cell metabolism [313]. To solve these problems, it is better to change the surface chemistry rather than the charge [314]. PEGlaytion could help partially repulse the binding of biomolecules from biological fluids, thus protecting the exposure of the targeting ligands [315]. The NPs could also be designed to attract more dysopsonins, such as albumin [316–318] or clusterin [319,320], on the surface to maintain longer circulation and better drug delivery efficiency. An advisable option is to manipulate the protein corona for brain-targeting. Zhang et al. modified an Aβ1–42 derived peptide onto the surface to absorb plasma apolipoproteins, and thus exposed the receptor-binding domain of apolipoproteins via the receptor-mediated transcytosis to cross BBB [312]. Tween 80 has also been shown to absorb serum apolipoproteins [321].
After crossing the BBB, CSF is another factor that leads to the formation of a protein corona, which obviously affects the targeting, cellular uptake, and drug release of NPs [322]. Wang et al. demonstrated both in vivo and in vitro, the formation of CSF protein corona on the surface of polystyrene NPs led to the loss of specific targeting neuronal cells [322]. Interestingly, Pinals et al. quantized the composition of protein corona on the surface of DNA-functionalized single-walled carbon nanotubes in plasma and CSF and found that the main types of proteins were involved in lipid binding, complement activation, and coagulation [323]. However, the knowledge of protein corona composition, formation mechanisms, and dynamics is still poor, which remains an obstacle in the clinical application of NPs.
In conclusion, this review highlights the potential of NPs to target different types of cells for the treatment of CNS diseases, indicating significant promise in the development of precise medicine. Nanotechnology enables flexible treatment strategies by combining drugs, enzymes, and gene tools, providing stability in circulation, improving capacity to cross the BBB, and allowing for regional and cell type targeting to enhance the disease conditions while reducing adverse effects on other tissues. Although several polymeric NPs and exosomes have undergone clinical trials at different stages, most nanodrugs for treating CNS diseases are still at the laboratory level. Therefore, further studies are required to assess the dynamics and biosafety of these nanodrugs before proceeding to clinical trials.
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Funding information: This work was supported by the GuangDong Basic and Applied Basic Research Foundation –Youth Fund (S.G., 2022A1515110230), and a grant from The Netherlands Organisation for Health Research and Development (ZonMw) (C.-X.Y., 459001004).
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Author contributions: S.G. and C.X.Y. conceptualized the review topic and outline. S.G. drafted the manuscript and C.X.Y. provided critical revisions and edits. Both authors contributed equally to the final version of the manuscript.
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Conflict of interest: The authors state no conflict of interest.
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- Dynamic recrystallization behavior and nucleation mechanism of dual-scale SiCp/A356 composites processed by P/M method
- High mechanical performance of 3-aminopropyl triethoxy silane/epoxy cured in a sandwich construction of 3D carbon felts foam and woven basalt fibers
- Applying solution of spray polyurea elastomer in asphalt binder: Feasibility analysis and DSR study based on the MSCR and LAS tests
- Study on the chronic toxicity and carcinogenicity of iron-based bioabsorbable stents
- Influence of microalloying with B on the microstructure and properties of brazed joints with Ag–Cu–Zn–Sn filler metal
- Thermohydraulic performance of thermal system integrated with twisted turbulator inserts using ternary hybrid nanofluids
- Study of mechanical properties of epoxy/graphene and epoxy/halloysite nanocomposites
- Effects of CaO addition on the CuW composite containing micro- and nano-sized tungsten particles synthesized via aluminothermic coupling with silicothermic reduction
- Cu and Al2O3-based hybrid nanofluid flow through a porous cavity
- Design of functional vancomycin-embedded bio-derived extracellular matrix hydrogels for repairing infectious bone defects
- Study on nanocrystalline coating prepared by electro-spraying 316L metal wire and its corrosion performance
- Axial compression performance of CFST columns reinforced by ultra-high-performance nano-concrete under long-term loading
- Tungsten trioxide nanocomposite for conventional soliton and noise-like pulse generation in anomalous dispersion laser cavity
- Microstructure and electrical contact behavior of the nano-yttria-modified Cu-Al2O3/30Mo/3SiC composite
- Melting rheology in thermally stratified graphene-mineral oil reservoir (third-grade nanofluid) with slip condition
- Re-examination of nonlinear vibration and nonlinear bending of porous sandwich cylindrical panels reinforced by graphene platelets
- Parametric simulation of hybrid nanofluid flow consisting of cobalt ferrite nanoparticles with second-order slip and variable viscosity over an extending surface
- Chitosan-capped silver nanoparticles with potent and selective intrinsic activity against the breast cancer cells
- Multi-core/shell SiO2@Al2O3 nanostructures deposited on Ti3AlC2 to enhance high-temperature stability and microwave absorption properties
- Solution-processed Bi2S3/BiVO4/TiO2 ternary heterojunction photoanode with enhanced photoelectrochemical performance
- Electroporation effect of ZnO nanoarrays under low voltage for water disinfection
- NIR-II window absorbing graphene oxide-coated gold nanorods and graphene quantum dot-coupled gold nanorods for photothermal cancer therapy
- Nonlinear three-dimensional stability characteristics of geometrically imperfect nanoshells under axial compression and surface residual stress
- Investigation of different nanoparticles properties on the thermal conductivity and viscosity of nanofluids by molecular dynamics simulation
- Optimized Cu2O-{100} facet for generation of different reactive oxidative species via peroxymonosulfate activation at specific pH values to efficient acetaminophen removal
- Brownian and thermal diffusivity impact due to the Maxwell nanofluid (graphene/engine oil) flow with motile microorganisms and Joule heating
- Appraising the dielectric properties and the effectiveness of electromagnetic shielding of graphene reinforced silicone rubber nanocomposite
- Synthesis of Ag and Cu nanoparticles by plasma discharge in inorganic salt solutions
- Low-cost and large-scale preparation of ultrafine TiO2@C hybrids for high-performance degradation of methyl orange and formaldehyde under visible light
- Utilization of waste glass with natural pozzolan in the production of self-glazed glass-ceramic materials
- Mechanical performance of date palm fiber-reinforced concrete modified with nano-activated carbon
- Melting point of dried gold nanoparticles prepared with ultrasonic spray pyrolysis and lyophilisation
- Graphene nanofibers: A modern approach towards tailored gypsum composites
- Role of localized magnetic field in vortex generation in tri-hybrid nanofluid flow: A numerical approach
- Intelligent computing for the double-diffusive peristaltic rheology of magneto couple stress nanomaterials
- Bioconvection transport of upper convected Maxwell nanoliquid with gyrotactic microorganism, nonlinear thermal radiation, and chemical reaction
- 3D printing of porous Ti6Al4V bone tissue engineering scaffold and surface anodization preparation of nanotubes to enhance its biological property
- Bioinspired ferromagnetic CoFe2O4 nanoparticles: Potential pharmaceutical and medical applications
- Significance of gyrotactic microorganisms on the MHD tangent hyperbolic nanofluid flow across an elastic slender surface: Numerical analysis
- Performance of polycarboxylate superplasticisers in seawater-blended cement: Effect from chemical structure and nano modification
- Entropy minimization of GO–Ag/KO cross-hybrid nanofluid over a convectively heated surface
- Oxygen plasma assisted room temperature bonding for manufacturing SU-8 polymer micro/nanoscale nozzle
- Performance and mechanism of CO2 reduction by DBD-coupled mesoporous SiO2
- Polyarylene ether nitrile dielectric films modified by HNTs@PDA hybrids for high-temperature resistant organic electronics field
- Exploration of generalized two-phase free convection magnetohydrodynamic flow of dusty tetra-hybrid Casson nanofluid between parallel microplates
- Hygrothermal bending analysis of sandwich nanoplates with FG porous core and piezomagnetic faces via nonlocal strain gradient theory
- Design and optimization of a TiO2/RGO-supported epoxy multilayer microwave absorber by the modified local best particle swarm optimization algorithm
- Mechanical properties and frost resistance of recycled brick aggregate concrete modified by nano-SiO2
- Self-template synthesis of hollow flower-like NiCo2O4 nanoparticles as an efficient bifunctional catalyst for oxygen reduction and oxygen evolution in alkaline media
- High-performance wearable flexible strain sensors based on an AgNWs/rGO/TPU electrospun nanofiber film for monitoring human activities
- High-performance lithium–selenium batteries enabled by nitrogen-doped porous carbon from peanut meal
- Investigating effects of Lorentz forces and convective heating on ternary hybrid nanofluid flow over a curved surface using homotopy analysis method
- Exploring the potential of biogenic magnesium oxide nanoparticles for cytotoxicity: In vitro and in silico studies on HCT116 and HT29 cells and DPPH radical scavenging
- Enhanced visible-light-driven photocatalytic degradation of azo dyes by heteroatom-doped nickel tungstate nanoparticles
- A facile method to synthesize nZVI-doped polypyrrole-based carbon nanotube for Ag(i) removal
- Improved osseointegration of dental titanium implants by TiO2 nanotube arrays with self-assembled recombinant IGF-1 in type 2 diabetes mellitus rat model
- Functionalized SWCNTs@Ag–TiO2 nanocomposites induce ROS-mediated apoptosis and autophagy in liver cancer cells
- Triboelectric nanogenerator based on a water droplet spring with a concave spherical surface for harvesting wave energy and detecting pressure
- A mathematical approach for modeling the blood flow containing nanoparticles by employing the Buongiorno’s model
- Molecular dynamics study on dynamic interlayer friction of graphene and its strain effect
- Induction of apoptosis and autophagy via regulation of AKT and JNK mitogen-activated protein kinase pathways in breast cancer cell lines exposed to gold nanoparticles loaded with TNF-α and combined with doxorubicin
- Effect of PVA fibers on durability of nano-SiO2-reinforced cement-based composites subjected to wet-thermal and chloride salt-coupled environment
- Effect of polyvinyl alcohol fibers on mechanical properties of nano-SiO2-reinforced geopolymer composites under a complex environment
- In vitro studies of titanium dioxide nanoparticles modified with glutathione as a potential drug delivery system
- Comparative investigations of Ag/H2O nanofluid and Ag-CuO/H2O hybrid nanofluid with Darcy-Forchheimer flow over a curved surface
- Study on deformation characteristics of multi-pass continuous drawing of micro copper wire based on crystal plasticity finite element method
- Properties of ultra-high-performance self-compacting fiber-reinforced concrete modified with nanomaterials
- Prediction of lap shear strength of GNP and TiO2/epoxy nanocomposite adhesives
- A novel exploration of how localized magnetic field affects vortex generation of trihybrid nanofluids
- Fabrication and physicochemical characterization of copper oxide–pyrrhotite nanocomposites for the cytotoxic effects on HepG2 cells and the mechanism
- Thermal radiative flow of cross nanofluid due to a stretched cylinder containing microorganisms
- In vitro study of the biphasic calcium phosphate/chitosan hybrid biomaterial scaffold fabricated via solvent casting and evaporation technique for bone regeneration
- Insights into the thermal characteristics and dynamics of stagnant blood conveying titanium oxide, alumina, and silver nanoparticles subject to Lorentz force and internal heating over a curved surface
- Effects of nano-SiO2 additives on carbon fiber-reinforced fly ash–slag geopolymer composites performance: Workability, mechanical properties, and microstructure
- Energy bandgap and thermal characteristics of non-Darcian MHD rotating hybridity nanofluid thin film flow: Nanotechnology application
- Green synthesis and characterization of ginger-extract-based oxali-palladium nanoparticles for colorectal cancer: Downregulation of REG4 and apoptosis induction
- Abnormal evolution of resistivity and microstructure of annealed Ag nanoparticles/Ag–Mo films
- Preparation of water-based dextran-coated Fe3O4 magnetic fluid for magnetic hyperthermia
- Statistical investigations and morphological aspects of cross-rheological material suspended in transportation of alumina, silica, titanium, and ethylene glycol via the Galerkin algorithm
- Effect of CNT film interleaves on the flexural properties and strength after impact of CFRP composites
- Self-assembled nanoscale entities: Preparative process optimization, payload release, and enhanced bioavailability of thymoquinone natural product
- Structure–mechanical property relationships of 3D-printed porous polydimethylsiloxane films
- Nonlinear thermal radiation and the slip effect on a 3D bioconvection flow of the Casson nanofluid in a rotating frame via a homotopy analysis mechanism
- Residual mechanical properties of concrete incorporated with nano supplementary cementitious materials exposed to elevated temperature
- Time-independent three-dimensional flow of a water-based hybrid nanofluid past a Riga plate with slips and convective conditions: A homotopic solution
- Lightweight and high-strength polyarylene ether nitrile-based composites for efficient electromagnetic interference shielding
- Review Articles
- Recycling waste sources into nanocomposites of graphene materials: Overview from an energy-focused perspective
- Hybrid nanofiller reinforcement in thermoset and biothermoset applications: A review
- Current state-of-the-art review of nanotechnology-based therapeutics for viral pandemics: Special attention to COVID-19
- Solid lipid nanoparticles for targeted natural and synthetic drugs delivery in high-incidence cancers, and other diseases: Roles of preparation methods, lipid composition, transitional stability, and release profiles in nanocarriers’ development
- Critical review on experimental and theoretical studies of elastic properties of wurtzite-structured ZnO nanowires
- Polyurea micro-/nano-capsule applications in construction industry: A review
- A comprehensive review and clinical guide to molecular and serological diagnostic tests and future development: In vitro diagnostic testing for COVID-19
- Recent advances in electrocatalytic oxidation of 5-hydroxymethylfurfural to 2,5-furandicarboxylic acid: Mechanism, catalyst, coupling system
- Research progress and prospect of silica-based polymer nanofluids in enhanced oil recovery
- Review of the pharmacokinetics of nanodrugs
- Engineered nanoflowers, nanotrees, nanostars, nanodendrites, and nanoleaves for biomedical applications
- Research progress of biopolymers combined with stem cells in the repair of intrauterine adhesions
- Progress in FEM modeling on mechanical and electromechanical properties of carbon nanotube cement-based composites
- Antifouling induced by surface wettability of poly(dimethyl siloxane) and its nanocomposites
- TiO2 aerogel composite high-efficiency photocatalysts for environmental treatment and hydrogen energy production
- Structural properties of alumina surfaces and their roles in the synthesis of environmentally persistent free radicals (EPFRs)
- Nanoparticles for the potential treatment of Alzheimer’s disease: A physiopathological approach
- Current status of synthesis and consolidation strategies for thermo-resistant nanoalloys and their general applications
- Recent research progress on the stimuli-responsive smart membrane: A review
- Dispersion of carbon nanotubes in aqueous cementitious materials: A review
- Applications of DNA tetrahedron nanostructure in cancer diagnosis and anticancer drugs delivery
- Magnetic nanoparticles in 3D-printed scaffolds for biomedical applications
- An overview of the synthesis of silicon carbide–boron carbide composite powders
- Organolead halide perovskites: Synthetic routes, structural features, and their potential in the development of photovoltaic
- Recent advancements in nanotechnology application on wood and bamboo materials: A review
- Application of aptamer-functionalized nanomaterials in molecular imaging of tumors
- Recent progress on corrosion mechanisms of graphene-reinforced metal matrix composites
- Research progress on preparation, modification, and application of phenolic aerogel
- Application of nanomaterials in early diagnosis of cancer
- Plant mediated-green synthesis of zinc oxide nanoparticles: An insight into biomedical applications
- Recent developments in terahertz quantum cascade lasers for practical applications
- Recent progress in dielectric/metal/dielectric electrodes for foldable light-emitting devices
- Nanocoatings for ballistic applications: A review
- A mini-review on MoS2 membrane for water desalination: Recent development and challenges
- Recent updates in nanotechnological advances for wound healing: A narrative review
- Recent advances in DNA nanomaterials for cancer diagnosis and treatment
- Electrochemical micro- and nanobiosensors for in vivo reactive oxygen/nitrogen species measurement in the brain
- Advances in organic–inorganic nanocomposites for cancer imaging and therapy
- Advancements in aluminum matrix composites reinforced with carbides and graphene: A comprehensive review
- Modification effects of nanosilica on asphalt binders: A review
- Decellularized extracellular matrix as a promising biomaterial for musculoskeletal tissue regeneration
- Review of the sol–gel method in preparing nano TiO2 for advanced oxidation process
- Micro/nano manufacturing aircraft surface with anti-icing and deicing performances: An overview
- Cell type-targeting nanoparticles in treating central nervous system diseases: Challenges and hopes
- An overview of hydrogen production from Al-based materials
- A review of application, modification, and prospect of melamine foam
- A review of the performance of fibre-reinforced composite laminates with carbon nanotubes
- Research on AFM tip-related nanofabrication of two-dimensional materials
- Advances in phase change building materials: An overview
- Development of graphene and graphene quantum dots toward biomedical engineering applications: A review
- Nanoremediation approaches for the mitigation of heavy metal contamination in vegetables: An overview
- Photodynamic therapy empowered by nanotechnology for oral and dental science: Progress and perspectives
- Biosynthesis of metal nanoparticles: Bioreduction and biomineralization
- Current diagnostic and therapeutic approaches for severe acute respiratory syndrome coronavirus-2 (SARS-COV-2) and the role of nanomaterial-based theragnosis in combating the pandemic
- Application of two-dimensional black phosphorus material in wound healing
- Special Issue on Advanced Nanomaterials and Composites for Energy Conversion and Storage - Part I
- Helical fluorinated carbon nanotubes/iron(iii) fluoride hybrid with multilevel transportation channels and rich active sites for lithium/fluorinated carbon primary battery
- The progress of cathode materials in aqueous zinc-ion batteries
- Special Issue on Advanced Nanomaterials for Carbon Capture, Environment and Utilization for Energy Sustainability - Part I
- Effect of polypropylene fiber and nano-silica on the compressive strength and frost resistance of recycled brick aggregate concrete
- Mechanochemical design of nanomaterials for catalytic applications with a benign-by-design focus
Articles in the same Issue
- Research Articles
- Preparation of CdS–Ag2S nanocomposites by ultrasound-assisted UV photolysis treatment and its visible light photocatalysis activity
- Significance of nanoparticle radius and inter-particle spacing toward the radiative water-based alumina nanofluid flow over a rotating disk
- Aptamer-based detection of serotonin based on the rapid in situ synthesis of colorimetric gold nanoparticles
- Investigation of the nucleation and growth behavior of Ti2AlC and Ti3AlC nano-precipitates in TiAl alloys
- Dynamic recrystallization behavior and nucleation mechanism of dual-scale SiCp/A356 composites processed by P/M method
- High mechanical performance of 3-aminopropyl triethoxy silane/epoxy cured in a sandwich construction of 3D carbon felts foam and woven basalt fibers
- Applying solution of spray polyurea elastomer in asphalt binder: Feasibility analysis and DSR study based on the MSCR and LAS tests
- Study on the chronic toxicity and carcinogenicity of iron-based bioabsorbable stents
- Influence of microalloying with B on the microstructure and properties of brazed joints with Ag–Cu–Zn–Sn filler metal
- Thermohydraulic performance of thermal system integrated with twisted turbulator inserts using ternary hybrid nanofluids
- Study of mechanical properties of epoxy/graphene and epoxy/halloysite nanocomposites
- Effects of CaO addition on the CuW composite containing micro- and nano-sized tungsten particles synthesized via aluminothermic coupling with silicothermic reduction
- Cu and Al2O3-based hybrid nanofluid flow through a porous cavity
- Design of functional vancomycin-embedded bio-derived extracellular matrix hydrogels for repairing infectious bone defects
- Study on nanocrystalline coating prepared by electro-spraying 316L metal wire and its corrosion performance
- Axial compression performance of CFST columns reinforced by ultra-high-performance nano-concrete under long-term loading
- Tungsten trioxide nanocomposite for conventional soliton and noise-like pulse generation in anomalous dispersion laser cavity
- Microstructure and electrical contact behavior of the nano-yttria-modified Cu-Al2O3/30Mo/3SiC composite
- Melting rheology in thermally stratified graphene-mineral oil reservoir (third-grade nanofluid) with slip condition
- Re-examination of nonlinear vibration and nonlinear bending of porous sandwich cylindrical panels reinforced by graphene platelets
- Parametric simulation of hybrid nanofluid flow consisting of cobalt ferrite nanoparticles with second-order slip and variable viscosity over an extending surface
- Chitosan-capped silver nanoparticles with potent and selective intrinsic activity against the breast cancer cells
- Multi-core/shell SiO2@Al2O3 nanostructures deposited on Ti3AlC2 to enhance high-temperature stability and microwave absorption properties
- Solution-processed Bi2S3/BiVO4/TiO2 ternary heterojunction photoanode with enhanced photoelectrochemical performance
- Electroporation effect of ZnO nanoarrays under low voltage for water disinfection
- NIR-II window absorbing graphene oxide-coated gold nanorods and graphene quantum dot-coupled gold nanorods for photothermal cancer therapy
- Nonlinear three-dimensional stability characteristics of geometrically imperfect nanoshells under axial compression and surface residual stress
- Investigation of different nanoparticles properties on the thermal conductivity and viscosity of nanofluids by molecular dynamics simulation
- Optimized Cu2O-{100} facet for generation of different reactive oxidative species via peroxymonosulfate activation at specific pH values to efficient acetaminophen removal
- Brownian and thermal diffusivity impact due to the Maxwell nanofluid (graphene/engine oil) flow with motile microorganisms and Joule heating
- Appraising the dielectric properties and the effectiveness of electromagnetic shielding of graphene reinforced silicone rubber nanocomposite
- Synthesis of Ag and Cu nanoparticles by plasma discharge in inorganic salt solutions
- Low-cost and large-scale preparation of ultrafine TiO2@C hybrids for high-performance degradation of methyl orange and formaldehyde under visible light
- Utilization of waste glass with natural pozzolan in the production of self-glazed glass-ceramic materials
- Mechanical performance of date palm fiber-reinforced concrete modified with nano-activated carbon
- Melting point of dried gold nanoparticles prepared with ultrasonic spray pyrolysis and lyophilisation
- Graphene nanofibers: A modern approach towards tailored gypsum composites
- Role of localized magnetic field in vortex generation in tri-hybrid nanofluid flow: A numerical approach
- Intelligent computing for the double-diffusive peristaltic rheology of magneto couple stress nanomaterials
- Bioconvection transport of upper convected Maxwell nanoliquid with gyrotactic microorganism, nonlinear thermal radiation, and chemical reaction
- 3D printing of porous Ti6Al4V bone tissue engineering scaffold and surface anodization preparation of nanotubes to enhance its biological property
- Bioinspired ferromagnetic CoFe2O4 nanoparticles: Potential pharmaceutical and medical applications
- Significance of gyrotactic microorganisms on the MHD tangent hyperbolic nanofluid flow across an elastic slender surface: Numerical analysis
- Performance of polycarboxylate superplasticisers in seawater-blended cement: Effect from chemical structure and nano modification
- Entropy minimization of GO–Ag/KO cross-hybrid nanofluid over a convectively heated surface
- Oxygen plasma assisted room temperature bonding for manufacturing SU-8 polymer micro/nanoscale nozzle
- Performance and mechanism of CO2 reduction by DBD-coupled mesoporous SiO2
- Polyarylene ether nitrile dielectric films modified by HNTs@PDA hybrids for high-temperature resistant organic electronics field
- Exploration of generalized two-phase free convection magnetohydrodynamic flow of dusty tetra-hybrid Casson nanofluid between parallel microplates
- Hygrothermal bending analysis of sandwich nanoplates with FG porous core and piezomagnetic faces via nonlocal strain gradient theory
- Design and optimization of a TiO2/RGO-supported epoxy multilayer microwave absorber by the modified local best particle swarm optimization algorithm
- Mechanical properties and frost resistance of recycled brick aggregate concrete modified by nano-SiO2
- Self-template synthesis of hollow flower-like NiCo2O4 nanoparticles as an efficient bifunctional catalyst for oxygen reduction and oxygen evolution in alkaline media
- High-performance wearable flexible strain sensors based on an AgNWs/rGO/TPU electrospun nanofiber film for monitoring human activities
- High-performance lithium–selenium batteries enabled by nitrogen-doped porous carbon from peanut meal
- Investigating effects of Lorentz forces and convective heating on ternary hybrid nanofluid flow over a curved surface using homotopy analysis method
- Exploring the potential of biogenic magnesium oxide nanoparticles for cytotoxicity: In vitro and in silico studies on HCT116 and HT29 cells and DPPH radical scavenging
- Enhanced visible-light-driven photocatalytic degradation of azo dyes by heteroatom-doped nickel tungstate nanoparticles
- A facile method to synthesize nZVI-doped polypyrrole-based carbon nanotube for Ag(i) removal
- Improved osseointegration of dental titanium implants by TiO2 nanotube arrays with self-assembled recombinant IGF-1 in type 2 diabetes mellitus rat model
- Functionalized SWCNTs@Ag–TiO2 nanocomposites induce ROS-mediated apoptosis and autophagy in liver cancer cells
- Triboelectric nanogenerator based on a water droplet spring with a concave spherical surface for harvesting wave energy and detecting pressure
- A mathematical approach for modeling the blood flow containing nanoparticles by employing the Buongiorno’s model
- Molecular dynamics study on dynamic interlayer friction of graphene and its strain effect
- Induction of apoptosis and autophagy via regulation of AKT and JNK mitogen-activated protein kinase pathways in breast cancer cell lines exposed to gold nanoparticles loaded with TNF-α and combined with doxorubicin
- Effect of PVA fibers on durability of nano-SiO2-reinforced cement-based composites subjected to wet-thermal and chloride salt-coupled environment
- Effect of polyvinyl alcohol fibers on mechanical properties of nano-SiO2-reinforced geopolymer composites under a complex environment
- In vitro studies of titanium dioxide nanoparticles modified with glutathione as a potential drug delivery system
- Comparative investigations of Ag/H2O nanofluid and Ag-CuO/H2O hybrid nanofluid with Darcy-Forchheimer flow over a curved surface
- Study on deformation characteristics of multi-pass continuous drawing of micro copper wire based on crystal plasticity finite element method
- Properties of ultra-high-performance self-compacting fiber-reinforced concrete modified with nanomaterials
- Prediction of lap shear strength of GNP and TiO2/epoxy nanocomposite adhesives
- A novel exploration of how localized magnetic field affects vortex generation of trihybrid nanofluids
- Fabrication and physicochemical characterization of copper oxide–pyrrhotite nanocomposites for the cytotoxic effects on HepG2 cells and the mechanism
- Thermal radiative flow of cross nanofluid due to a stretched cylinder containing microorganisms
- In vitro study of the biphasic calcium phosphate/chitosan hybrid biomaterial scaffold fabricated via solvent casting and evaporation technique for bone regeneration
- Insights into the thermal characteristics and dynamics of stagnant blood conveying titanium oxide, alumina, and silver nanoparticles subject to Lorentz force and internal heating over a curved surface
- Effects of nano-SiO2 additives on carbon fiber-reinforced fly ash–slag geopolymer composites performance: Workability, mechanical properties, and microstructure
- Energy bandgap and thermal characteristics of non-Darcian MHD rotating hybridity nanofluid thin film flow: Nanotechnology application
- Green synthesis and characterization of ginger-extract-based oxali-palladium nanoparticles for colorectal cancer: Downregulation of REG4 and apoptosis induction
- Abnormal evolution of resistivity and microstructure of annealed Ag nanoparticles/Ag–Mo films
- Preparation of water-based dextran-coated Fe3O4 magnetic fluid for magnetic hyperthermia
- Statistical investigations and morphological aspects of cross-rheological material suspended in transportation of alumina, silica, titanium, and ethylene glycol via the Galerkin algorithm
- Effect of CNT film interleaves on the flexural properties and strength after impact of CFRP composites
- Self-assembled nanoscale entities: Preparative process optimization, payload release, and enhanced bioavailability of thymoquinone natural product
- Structure–mechanical property relationships of 3D-printed porous polydimethylsiloxane films
- Nonlinear thermal radiation and the slip effect on a 3D bioconvection flow of the Casson nanofluid in a rotating frame via a homotopy analysis mechanism
- Residual mechanical properties of concrete incorporated with nano supplementary cementitious materials exposed to elevated temperature
- Time-independent three-dimensional flow of a water-based hybrid nanofluid past a Riga plate with slips and convective conditions: A homotopic solution
- Lightweight and high-strength polyarylene ether nitrile-based composites for efficient electromagnetic interference shielding
- Review Articles
- Recycling waste sources into nanocomposites of graphene materials: Overview from an energy-focused perspective
- Hybrid nanofiller reinforcement in thermoset and biothermoset applications: A review
- Current state-of-the-art review of nanotechnology-based therapeutics for viral pandemics: Special attention to COVID-19
- Solid lipid nanoparticles for targeted natural and synthetic drugs delivery in high-incidence cancers, and other diseases: Roles of preparation methods, lipid composition, transitional stability, and release profiles in nanocarriers’ development
- Critical review on experimental and theoretical studies of elastic properties of wurtzite-structured ZnO nanowires
- Polyurea micro-/nano-capsule applications in construction industry: A review
- A comprehensive review and clinical guide to molecular and serological diagnostic tests and future development: In vitro diagnostic testing for COVID-19
- Recent advances in electrocatalytic oxidation of 5-hydroxymethylfurfural to 2,5-furandicarboxylic acid: Mechanism, catalyst, coupling system
- Research progress and prospect of silica-based polymer nanofluids in enhanced oil recovery
- Review of the pharmacokinetics of nanodrugs
- Engineered nanoflowers, nanotrees, nanostars, nanodendrites, and nanoleaves for biomedical applications
- Research progress of biopolymers combined with stem cells in the repair of intrauterine adhesions
- Progress in FEM modeling on mechanical and electromechanical properties of carbon nanotube cement-based composites
- Antifouling induced by surface wettability of poly(dimethyl siloxane) and its nanocomposites
- TiO2 aerogel composite high-efficiency photocatalysts for environmental treatment and hydrogen energy production
- Structural properties of alumina surfaces and their roles in the synthesis of environmentally persistent free radicals (EPFRs)
- Nanoparticles for the potential treatment of Alzheimer’s disease: A physiopathological approach
- Current status of synthesis and consolidation strategies for thermo-resistant nanoalloys and their general applications
- Recent research progress on the stimuli-responsive smart membrane: A review
- Dispersion of carbon nanotubes in aqueous cementitious materials: A review
- Applications of DNA tetrahedron nanostructure in cancer diagnosis and anticancer drugs delivery
- Magnetic nanoparticles in 3D-printed scaffolds for biomedical applications
- An overview of the synthesis of silicon carbide–boron carbide composite powders
- Organolead halide perovskites: Synthetic routes, structural features, and their potential in the development of photovoltaic
- Recent advancements in nanotechnology application on wood and bamboo materials: A review
- Application of aptamer-functionalized nanomaterials in molecular imaging of tumors
- Recent progress on corrosion mechanisms of graphene-reinforced metal matrix composites
- Research progress on preparation, modification, and application of phenolic aerogel
- Application of nanomaterials in early diagnosis of cancer
- Plant mediated-green synthesis of zinc oxide nanoparticles: An insight into biomedical applications
- Recent developments in terahertz quantum cascade lasers for practical applications
- Recent progress in dielectric/metal/dielectric electrodes for foldable light-emitting devices
- Nanocoatings for ballistic applications: A review
- A mini-review on MoS2 membrane for water desalination: Recent development and challenges
- Recent updates in nanotechnological advances for wound healing: A narrative review
- Recent advances in DNA nanomaterials for cancer diagnosis and treatment
- Electrochemical micro- and nanobiosensors for in vivo reactive oxygen/nitrogen species measurement in the brain
- Advances in organic–inorganic nanocomposites for cancer imaging and therapy
- Advancements in aluminum matrix composites reinforced with carbides and graphene: A comprehensive review
- Modification effects of nanosilica on asphalt binders: A review
- Decellularized extracellular matrix as a promising biomaterial for musculoskeletal tissue regeneration
- Review of the sol–gel method in preparing nano TiO2 for advanced oxidation process
- Micro/nano manufacturing aircraft surface with anti-icing and deicing performances: An overview
- Cell type-targeting nanoparticles in treating central nervous system diseases: Challenges and hopes
- An overview of hydrogen production from Al-based materials
- A review of application, modification, and prospect of melamine foam
- A review of the performance of fibre-reinforced composite laminates with carbon nanotubes
- Research on AFM tip-related nanofabrication of two-dimensional materials
- Advances in phase change building materials: An overview
- Development of graphene and graphene quantum dots toward biomedical engineering applications: A review
- Nanoremediation approaches for the mitigation of heavy metal contamination in vegetables: An overview
- Photodynamic therapy empowered by nanotechnology for oral and dental science: Progress and perspectives
- Biosynthesis of metal nanoparticles: Bioreduction and biomineralization
- Current diagnostic and therapeutic approaches for severe acute respiratory syndrome coronavirus-2 (SARS-COV-2) and the role of nanomaterial-based theragnosis in combating the pandemic
- Application of two-dimensional black phosphorus material in wound healing
- Special Issue on Advanced Nanomaterials and Composites for Energy Conversion and Storage - Part I
- Helical fluorinated carbon nanotubes/iron(iii) fluoride hybrid with multilevel transportation channels and rich active sites for lithium/fluorinated carbon primary battery
- The progress of cathode materials in aqueous zinc-ion batteries
- Special Issue on Advanced Nanomaterials for Carbon Capture, Environment and Utilization for Energy Sustainability - Part I
- Effect of polypropylene fiber and nano-silica on the compressive strength and frost resistance of recycled brick aggregate concrete
- Mechanochemical design of nanomaterials for catalytic applications with a benign-by-design focus
