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Hepatotoxicity of nanomaterials: From mechanism to therapeutic strategy

  • Chengtian Gao , Mingdong Wang , Yali Zheng , Liang Zhang , Jiawei He , Bosen Liu , Xinhua Lin , Jingsong Mao EMAIL logo and Zhanxiang Wang EMAIL logo
Published/Copyright: August 6, 2024
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Nanotechnology Reviews
From the journal Nanotechnology Reviews Volume 13 Issue 1

Abstract

Most nanoparticles are metabolized and accumulated in the liver; therefore, this review, based on most data collected from PubMed.gov between 2012 and 2023 with the keywords “nanomaterials induced hepatotoxicity,” aims to elucidate the mechanism of nanoparticles leading to liver injury and propose relevant strategies. We discuss the biomedical approaches and strategies for mitigating liver injury, including 1) principle and recommendation of material selection; 2) nanoparticle surface modulation; 3) strategies inspired by virus and other biological phenomenon; and 4) drug and other possible adjunctive strategies. The optimal design of nanomaterials and therapeutic strategies to attenuate hepatotoxicity is critical for the development of nanomedicine.

Graphical abstract

Keywords: nanomaterial; hepatotoxicity; liver injury

1 Introduction

Nanomaterials have been widely used in the medical field to deliver drugs and improve therapeutic efficacy due to their unique nanoscale size [1]. Nanoparticles can improve vascular permeability and favor the enhanced permeability and retention (EPR) effect, which is very advantageous in the treatment of inflammation or cancer with non-targeted drugs. In addition, bio-inspired nanotechnology, including vesicles, exosomes, or engineered cell membranes, endows the active-targeting capability to the specific lesion [2]. The incorporation of molecular imaging probes could also monitor the delivery and release behavior of nanomaterials using computed tomography (CT), magnetic resonance imaging (MRI), ultrasound (US), fluorescence imaging (FL), photoacoustic imaging (PAI), and some emerging imaging methods. Importantly, some nanomaterials can act as sensitizers to improve efficacy and increase bioavailability, thereby reducing tumor drug resistance. The development of multifunctional nanomaterials also endows nanocarriers with other biological effects, such as light response (photothermal therapy or photodynamic therapy), ultrasonic response (sonodynamic therapy or high-intensity focused ultrasound), magnetic response (magnetic hyperthermia), and other synergistic therapeutic effects.

However, there are still safety concerns, among which are the reactive oxygen species (ROS). Besides the immediate cytotoxicity to damage cell components, ROS also triggers signal pathways to cause necrosis, necroptosis, or apoptosis [3]. Nanomaterial-induced inflammation, both acute and chronic, increases the risk of liver fibrosis and pathological changes [4]. Genotoxicity, including damage to DNA structure, revealed potential carcinogenicity. Some evidence indicates that nanomaterial-induced epigenetic effects include abnormal DNA methylation and histone modifications, which could act as potential biomarkers for predicting the adverse effects of nanomaterials [5].

To address these hidden hazards, sufficient efforts are being made to focus on physical and chemical strategies. Rod-shaped nanoparticles seemed to reduce the uptake by the liver compared to spherical nanoparticles [6]. Various aspect ratios of different shapes have an influence on the retention time in organs [7]. Enhanced elasticity and deformability also help nanoparticles avoid recognition and sequestration by the MPS (mononuclear phagocyte system) [8]. Even the same element, with a different valence, displayed a disparity in hepatotoxicity. Under the same injected dose, 70% MnO nanoparticles can be metabolized by the liver within 48 h [9], while only approximately 50% Mn3O4 is eliminated in 1.5 weeks [10], indicating the metabolic process of nanoparticles in vivo is complex, and its safety requires a comprehensive evaluation.

Given that most nanomaterials are sequestered by the liver, we mainly review how to mitigate the damages of nanomaterials to the liver on a biological basis, including materials selection, surface modification of nanomaterials, bio-inspired construction, and some adjunctive or strategies, to provide ideas for the clinical translation of nanomedicine (Scheme 1).

Scheme 1 Illustration of strategies for nanomaterial-induced hepatotoxicity.
Scheme 1

Illustration of strategies for nanomaterial-induced hepatotoxicity.

2 Mechanism of nanomaterial-induced hepatotoxicity

Conventional drug-induced hepatotoxicity is mainly based on metabolism or accumulation of the drug in hepatocytes, with activation of CD4 or cytotoxic CD8+ T-cells [11] leading to antigenic binding, which triggers an immune response, whereas nanomedicine-induced hepatotoxicity is characterized by free radical generation and oxidative stress [12,13]. Therefore, we focus here on ROS and inflammation, with a broader discussion of other related issues.

2.1 ROS and inflammation

Hepatotoxicity is often the most significant safety concern associated with nanomaterial toxicity. The main cause of hepatotoxicity is the production of ROS, such as mono-linear oxygen species, superoxide anion radicals, oxygen radicals, peroxide ions, hydrogen peroxide, and hydroxyl radicals, which enter cells via endocytosis and trigger a series of oxidative stress-related events [14]. In liver LO2 cells, mitochondria-derived ROS were found to activate the NOD-like receptor protein 3 (NLRP3) inflammasome, which promotes caspase-1-dependent thermal apoptosis [15]. ROS-induced mitochondrial swelling, loss of inner membrane and cristae, and increased mRNA levels of caspase-12, a marker of mitochondrial-caspase pathway activation, were found in the livers of normal mice exposed to SiNPs, confirming mitochondrial damage and apoptotic signaling. Upregulation of p53, Bax, and cleaved caspase-3 expression, as well as down-regulation of Bcl-2 and caspase-3 levels, was also detected when human and rat hepatocytes were exposed to SiO2 nanoparticles [16].

The vast majority of nanodrugs are exogenous chemicals that inevitably cause immune recognition and inflammatory response. In HepG2 cells, nanoparticles activate cellular stress response signaling pathways, including mitogen-activated protein kinase (MAPK) and NF-κB (nuclear factor-κ-gene binding) signaling pathways, with significant changes in the phosphorylation levels of stress-activated protein kinase such as ERK1/2, p38, and JNK. The levels of TNF, a pro-inflammatory factor that promotes lymphocyte infiltration and necrosis, and IL-8, a chemokine that recruits and activates neutrophils, were also significantly increased, whereas the expression of A20, an anti-inflammatory gene, was suppressed [17]. Similarly, mice exposed to multi-walled carbon nanotubes exhibited severe inflammatory cell infiltration in the portal vein region, cellular necrosis and localized necrosis, mitochondrial damage, and lysis.

Changes in gene expression involving the antigen processing and presentation pathways, cholesterol biosynthesis, the IL-6 signaling pathway, the cell cycle, and the metabolism of cytochrome P450 to xenobiotics were detected across genomes, with TNF-α and NF-κB signaling pathways showing the most significant changes [18]. Exposure of C57BL/6 mice to peptide-functionalized gold nanorods resulted in a decrease in the activity of the anti-inflammatory genes Arg-1 and IL-4, while at the same time, the levels of TNF-α, a marker of M1 macrophages, were very high, suggesting activation of this cell, and Arg-1 is a marker of M2 macrophages. The time course of the nanoparticle-induced inflammatory response was also investigated. Injected silica nanoparticles activate a variety of inflammatory signaling pathways at different time points, including the G1-S cell cycle, IL-10, IL-6 pathways, phagocytosis-related inflammatory pathways, and Th-17-derived pathways [19]. These results indicate that there are different time windows for specific blocking strategies. However, two questions need to be answered:

  1. Does human nanomaterial-induced hepatotoxicity also share similar physiological courses?

  2. Do different materials or the same material in different doses and states also trigger similar changes in vivo?

Inflammation caused by ROS is difficult to distinguish from other types of inflammation. However, persistent reports of the NF-κB pathway and TNF-α factor may highlight key locations for blocking the inflammatory cascade. NF-κB nuclear factor and erythroid 2-related factor (NRF2) may be crucial to indicate whether the level of ROS is out of control [20]. In addition, inhibition of M1 macrophage activity may be another strategy to reduce nanoparticle-induced hepatotoxicity (Figure 1). Mitochondrial protectants can also be considered in the future design of biomedical nanoparticles.

Figure 1 The genetic and epigenetic pathways and other variations in nanomaterial- induced hepatotoxicity.
Figure 1

The genetic and epigenetic pathways and other variations in nanomaterial- induced hepatotoxicity.

2.2 Lipoapoptosis

Liposomes, the most common organic materials used in biological applications, are well-documented to be hepatotoxic upon systemic administration of cationic liposomes, exhibiting significant liver biochemical function abnormalities and histological damage [21]. In Gregory’s report, inflammatory extracellular vesicles (EVs) containing expression of tumor necrosis factor-associated apoptosis-inducing ligand (TRAIL) can be induced by lipid in death receptor 5 (DR5)-dependent manner [22]. DR5 is a promoter that regulates hepatocyte lipoapoptosis and inflammatory signaling [23], and the knockdown of DR5 in vivo could significantly reduce hepatocyte lipotoxicity. Blocking Rho-associated-coiled-containing protein kinase-1 (ROCK1), which promoted the release of EVs, could reduce lipid-induced liver damage [24]. Receptor-interacting protein kinase 1 (RIP1) also plays an important role in the expression of pro-inflammatory factors, such as the typical M1 macrophage markers IL-1β or IL-6, which act as pro-inflammatory factors and contribute to the inflammatory response in hepatocytes. From this perspective, the hepatotoxicity of EV applications deserves more attention. As emerging bio-inspired materials, EVs function as a drug delivery system that can deliver therapeutic drugs or imaging probes to designated disease sites through active targeting. Besides, the nanoscale size of EVs facilitates their passive targeting ability, which improves the potency of drug delivery and promotes diagnostic and therapeutic efficacy. Considering the potential role of lipid-induced EVs in the activation of pro-inflammatory macrophage, an in-depth assessment of the role of EVs in hepatotoxicity, particularly in the regulation of hepatic biochemical factors, is essential for biological applications.

However, though anti-DR5 chimeric antibodies work for tumor suppression [25], there are no reports on blocking DR5 to mitigate nanoparticle lipotoxicity. It remains to be further explored whether any small molecule or monoclonal antibody to DR5 can effectively inhibit hepatocyte lipoapoptosis in vivo (Figure 2).

Figure 2 The mechanism of DR5-introduced lipoapoptosis. Lipid activates DR5, which regulates the expression of TRAIL and RIP1, causing inflammation and activating M1 macrophages. ROCK1 contributes to the release of TRAIL.
Figure 2

The mechanism of DR5-introduced lipoapoptosis. Lipid activates DR5, which regulates the expression of TRAIL and RIP1, causing inflammation and activating M1 macrophages. ROCK1 contributes to the release of TRAIL.

2.3 Genotoxicity

The genotoxicity of nanoparticles has also caused great concerns. Researchers have found that titanium oxide nanoparticles deposited in liver DNA not only insert DNA base pairs but also bind to DNA nucleotides and alter the secondary structure of DNA. Furthermore, high doses of nano-anatase TiO2 cause DNA breakage in hepatocytes [26]. Morphological scans show markedly reduced nuclei, nuclear vacuolization, and chromatin margination [27]. In HepG2 cells exposed to TiO2 nanoparticles, DNA repair-related genes (including p53, MDM2, GADD 45α, and p21) were dramatically upregulated, and oxidative damage led to DNA strand breaks [28]. In another example, CuO nanoparticles induced the expression of 8-hydroxy-2′-deoxyguanosine(8-OH-dG), an indicator of oxidative DNA damage in the liver [29]. Nanoparticle-induced genotoxicity has also been reported in silica and gold nanoparticles, where significant DNA damage was detected after intravenous injection, especially in the smaller nanoparticles [19,30]. All of these studies suggest that DNA damage caused by nanomaterials may lead to carcinogenicity and severe cellular degeneration (Figure 3).

Figure 3 The genotoxicity induced by nanomaterials, including DNA cleavage, DNA strands break, DNA secondary structure damage, and DNA repair system damage.
Figure 3

The genotoxicity induced by nanomaterials, including DNA cleavage, DNA strands break, DNA secondary structure damage, and DNA repair system damage.

3 Material selection for low hepatotoxicity in biological view

Material strategies to reduce hepatotoxicity are as follows: (1) selecting materials that can be degraded by more pathways in the body; (2) selecting materials that can be rapidly metabolized in liver; (3) targeting the site of the lesions, thus reducing the total amount of drugs; and (4) sustained and stable release of the drug, thus keeping the blood level low.

The longer metabolism time of iron nanoparticles compared to zinc or manganese is due to a later breakdown in the liver, particularly in Kupffer cells [31]. For organic materials, lipid H, lipid M, lipid P, lipid Q, lipid N, and lipid Y showed significantly less accumulation in the liver after intramuscular injection compared to lipid MC3. However, it must be recognized that these molecules, from the degradation of organic materials like hydrogel and lipids, would increase the liver burden [32,33] and aggravate hepatopathy [34].

Gelatin nanoparticles are good colloidal drug carriers for anticancer chemotherapy, which have, e.g., an arginine–glycine–aspartic acid sequence identified by integrin αV (especially αVβ3). Integrin αV is highly expressed in tumor vasculature and endothelial cells lining tumor tissues but less so in normal organs [2]. From this, gelatin-based nanocarriers (GNPs) are also suited for the central nervous system as they may passively target the injured brain tissue or brain tumors upregulated by gelatinases A and B [35]. Organic nanomaterials have advantages such as high loading capacity and low hepatotoxicity, but they also have drawbacks like limited stability. In contrast, the opposite is metal-based nanomaterials. To mitigate hepatotoxicity, metal–organic frameworks (MOFs) have been designed. In 2006, it was discovered that MOFs can hold a high concentration of medication and release them steadily over time. Stability and stiffness from the metals enable a high drug loading, while the safety and porosity of organic components ensure tunable release behaviors [36]. Works including stimuli-responsive MOF framework (e.g., pH/ROS dual-sensitive) and tumor-designed MOFs with decoys have reported better therapeutic efficacy of MOFs with minimal damage to normal liver cells due to improved drug efficiency, controlled drug release, prolonged duration of action, and drug targeting [3,31,35–39] (Table 1).

Table 1

Comparison of different hypotoxic materials for the nanocarriers and their mechanism to reduce hepatotoxicity

Nanocarrier Categories Mechanism Subjects/cells Ref.
Zinc oxide-engineered nanoparticles Inorganic materials Degraded by MPS in the endolysosomal compartments of phagocytic cells BALB/c mice and Wistar–Han rats [9,31,37]
MnO Inorganic materials Unknown hepatobiliary clearance pathway Balb/c female mice [9]
Lipid H Organic material Degraded by MPS or serum protein Sprague–Dawley rats [38]
cRGD–chitosan–gold nanoparticles Organic materials (gelatin and hydrogel) Targeting delivery MCF-7 and HUVEC cells [2]
5-FAM/FA/TP@Fe-MIL-101 Composite materials (MOF) Targeting delivery Balb/c nude mice [39]
γ-CD-MOF Composite materials Sustained drug release L929 cells [40]
PCP-Mn-DTA@GOx@1-MT Composite materials (MOF) Targeting delivery C57BL/6 mice and Balb/c mice [41]

4 Engineering strategies for modifying nanoparticles

Surface engineering can be achieved by targeting while preventing non-specific interactions. There are two common ways to alter the surface of nanomaterials: non-covalent conjugation and covalent conjugation, both of which can be used to target lesions and mitigate their hepatotoxicity.

4.1 PEGylation and conditional release modulation

When the nanomedicines enter the body, the surface coating of its nanoparticles with polyethylene glycol (PEG: PEGylation) prevents the nanoparticles from aggregating in the blood circulation and has a phagocytic effect. The MPS in the body has many opsonin-recognizing receptors on the cell surface, which can form a hydration cloud that sterically prevents nanomaterials from binding or interacting with the PEG chains immobilized on the surface of the nanomaterials, preventing the nanomaterials from combining or interacting with other nanomaterials or blood components from a three-dimensional structure [42,43]. The molecular weight (MW) and surface density of PEG are the main parameters affecting interactions and nanodrug metabolism; an MW greater than 2–10 kDa is essential for a low recognition level of MPS, partly due to less protein absorption [44,45].

PEG with MW less than 20 kDa are primarily metabolized in the renal system, whereas those more than 30 kDa are metabolized in the liver [46,47]. When PEGylated gold NPs are administered systemically, the circulation half-life is prolonged with MW increase between 2 and 10 kDa MW [48]. Also, it was shown that liver uptake of 5 kDa PEG was higher compared to 20 kDa PEG-coated NPs. In a subsequent study, NPs coated with 20 kDa PEG decreased hepatic uptake in vivo compared to NPs coated with 5 kDa PEG, resulting in prolonged circulation time [49]. Increased surface PEG density leads to PEG chain overlap and constitutes a maskant, which decreases the uptake of MPS cells by the liver [50,51]. Alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase level, and histopathological evaluation are the main indicators that support the hepatoprotective effect of PEG-coated gold nanomaterials [52]. However, besides the high cost, the shortcomings of conventional PEGylation involve obvious loss of efficacy, as the PEG chains may occupy the active sites of drugs [53,54], and most polyacids are difficult to degrade enzymatically [55].

High lactic acid level leads to paradoxically acidic extracellular and intracellular tumor microenvironments in almost all tumors. In order to coat nanomaterials with pH-responsive layers used to regulate the release of cancer chemotherapeutic drugs, researchers have coated the nanomaterials with poly(β-amino ester)(PBAE), whose tertiary amine residues may be ionized in an acidic environment. In BALB/c nude mice injected with A549 cells, doxorubicin(DOX)-coated PBAE nanomaterials were more efficiently absorbed by cancer tissues despite causing modest levels of hepatic function indicators (ALT and AST) [56].

In addition, the surface of nanomaterials can be modified with ligands (e.g., peptides, nucleic aptamers, polysaccharides, or antibodies) that recognize antigens expressed on the surface of diseased cells to improve the specificity of nanodrug delivery. In SCID Beige mice, gelatin nanoparticle surface-modified with an epidermal growth factor receptor (EGFR)-targeting peptide were almost double as effective as PEG-modified or untreated nanoparticles for tumor targeting without adding any additional hepatotoxicity [57]. High levels of programmed death ligand protein-1(PD-L1) expressed in cancer cells are associated with immune evasion and a dismal prognosis. Hyperbranched, multivalent poly(amidoamine) dendrimers can be used to bind the PD-1/PD-L1 antibody. Nanoparticle–antibody conjugates promoted T-cell antitumor immunity while reducing tumor chemoresistance to DOX compared to PD-L1 human antibody and showed no additional hepatotoxicity [58].

4.2 Bioinspired cell membrane coating nanotechnology

Cell membrane coating nanotechnology further advances surface modification [59,60]. The particle cores of cell membrane-coated nanoparticles are covered by natural or artificial cell membranes and have some of the intrinsic features of source cells (Figure 4) [61].

Figure 4 A drawing of nanoparticles with cell membrane coatings. Membrane sources for coating nanoparticles. Each cell membrane type may use different features to offer functionality to nanoparticulate cores, the substance of which can vary depending on the application [53]. Reproduced with permission from the study of Fang et al. [61]. Copyright 2018, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Figure 4

A drawing of nanoparticles with cell membrane coatings. Membrane sources for coating nanoparticles. Each cell membrane type may use different features to offer functionality to nanoparticulate cores, the substance of which can vary depending on the application [53]. Reproduced with permission from the study of Fang et al. [61]. Copyright 2018, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Erythrocytes were the first cells of origin to be utilized to encapsulate cell membranes with nanoparticles and are also the most intensively researched cells in this field [62,63]. Erythrocytes are the best source of nanocarriers due to (1) the lack of organelles in this cell, (2) circulation in the blood for up to 4 months, and (3) the detoxification activity of its surface proteins. The liver is the primary organ responsible for the detoxification of hemoglobin and the majority of chemotherapeutic drugs. The toxin affinity of the erythrocyte membrane may be used to prevent the hemolytic impact of hemolysin [64], though mechanisms are not clear. RBC-membrane-coated nanomaterials carrying doxorubicin significantly increased the survival rates of C57BL/6 mice carrying EL4 cells compared to free doxorubicin administration in the same dose, while no significant increase in ALT and AST was detected, and low IL-6 levels indicated no acute liver and systemic responses [65]. Similar findings revealed that RBC membranes could bind DOX, thereby reducing its harmful activity, and their complexes are stable in serum, most likely due to the surface charge of RBC surface proteins of membrane-coated nanoparticles. In contrast to the total retention of PEG-coated nanoparticles of 11% (24 h after injection) and 2% (48 h after injection), the retention of RBC membrane-coated nanoparticles exhibited 29 and 16%, showing that RBC membrane coating was efficient in evading the reticuloendothelial system (RES) [62].

Besides RBC membranes, other sources such as leukocyte membranes, stem cell membranes, endothelial cell membranes, cancer cell membranes, and even hybrid cell membranes have shown promise for liver protection in the way of increasing the targeting of drug delivery; immune modulation or direct binding ability by surface proteins [58,66–68]. However, a certain amount of antigens or even autoantigens may be present in T/B cells and cause serious immune response [69–71].

5 Biological camouflage strategy

5.1 Hijacking cells

Besides MPS, the tumor vasculature and blood–brain barrier (BBB) remain barriers to nanodrug delivery [72]. A strategy to hijack cells in vivo across vessel barriers and to target the inflamed lesion can dramatically alleviate hepatotoxicity because of little liver uptake. Liberal amounts, excellent locomotion ability, and 8 h half-time make neutrophils the most popular platform for the strategy [73–75]. Among PEG, IgG, and anti CD11b antibody-modified nanoparticles, the CD11b Abs decorated nanomaterials have shown the highest uptake specificity of neutrophils. Under the conditions of acute inflammation induced by photodynamic therapy, the accumulation of CD11b nanoparticles was 35 times higher than PEG-modified nanoparticles in lesions [76]. TA99 administration further enhances the therapeutic effect due to antibody-dependent cellular cytotoxicity mechanisms [75], and the pretreatment of TA99 in a mice model of melanoma has the following three merits: (1) promoting neutrophils to infiltrate into tumors; (2) significantly increased uptake radio of the nanoparticles by neutrophil, and thus (3) improved the survival rate (Figure 5) [77].

Figure 5 Diagram of hijacking cell strategy. Neutrophils hijacked by nanoparticles in the bloodstream are attracted by chemokines and then bind to tumor cells with TA99.
Figure 5

Diagram of hijacking cell strategy. Neutrophils hijacked by nanoparticles in the bloodstream are attracted by chemokines and then bind to tumor cells with TA99.

5.2 Transient depletion of host Kupffer cells

Kupffer cells in hepatic sinusoids are resident macrophages that play a major role in phagocytosing nanoparticles in the bloodstream, consistent with the role of MPS [78]. A previous study has shown that transient depletion of host Kupffer could alleviate liver injury induced by alcohol in rats [79]. This strategy is equally effective for nanoparticle-induced hepatotoxicity. Substances including gadolinium chloride [80], methyl palmitate [81], dextran sulfate (500 kDa) [82], carrageenan [83], and clodronate liposomes [78] were used for transient depletion of Kupffer cells. In mice models bearing SUIT-2 cells (a human pancreatic adenocarcinoma cell line), injection of clodronate caused almost complete depletion of Kupffer cells on Days 2 and 3, and the amount of Kupffer cells started to recover on Day 5. Clodronate pretreatment reduced the accumulation of doxorubicin from 6.4  to 4.7 μg/g-tissue by Kupffer cell depletion [84]. However, recovery in cell mass does not mean recovery in cell quality. All these studies did not present convincing evidence that regenerated cells have no genetic damage and epigenetic changes to further induce cirrhosis or malignant transformation. Notably, depletion of Kupffer cells may lead to significant accumulation of drugs in other organs (e.g., spleen, lung, heart, or kidney). Whether this strategy poses a risk by disrupting the immune system, especially for those with immunologic deficiency and serious infection, needs to be confirmed.

6 Drugs and other possible strategies

In addition to the development of nanoparticles, combination therapy with other drugs and methods (e.g., ultrasound or photodynamic therapy) may be considered to alleviate hepatotoxicity. Standard methods of clinical treatment of drug-induced liver injury include N-acetylcysteine and corticosteroids [85,86]. However, there are no specific treatments for nanomaterial-induced toxicity.

6.1 Hepatoprotectors

There are a number of hepatoprotective species, including vitamin E (Vit E), α-lipoic acid (ALA), quercetin (Qur), and arginine (Arg), which act as antioxidants mainly by inhibiting the peroxidation of fatty acids and by increasing the levels of cysteine and glutathione in the liver [87–89]. In a study aimed at comparing the hepatoprotective effects of these four antioxidants with those of melanin, melanin was shown to be the most significant in ameliorating gold nanoparticle-induced hepatic dysfunction, as measured by a comprehensive evaluation of all indicators of liver functions in experimental male rats [90]. ALA also downregulated iNOS, which is responsible for nitrosative stress, and reduced the overexpression levels of apoptotic genes C-Jun and C-Myc in the liver [91]. Moreover, ALA reduces CNP accumulation in hepatic tissue by unknown mechanisms [91].

In terms of natural extracts, beetroot juice has also shown powerful liver protective effects and anti-inflammatory and anti-mutagenic properties [92]. The hepatoprotective effect of beetroot juice is supported by the fact that the effects of oxidative stress on silver nanoparticle-induced liver injury in rats can be attenuated by maintaining the activity of antioxidant systems (e.g., SOD and CAT) and by increasing the amount of GSH in the liver, and by the improvement in the expression of p53 and anti-apoptotic Bcl-d2, with little DNA fragmentation [92] supported the hepatoprotective effects of beetroot juice. However, it is unclear what played a major role in this effect. Grape seed proanthocyanidin extract (GSE) also alleviated TiO2 nanoparticle-induced liver injury and oxidative stress in rats. GSE treatment mediated the expressions of TLR-4, NF-κB, NIK, and TNF-α genes and maintained a high level of GSH in the liver.

Despite various advances, it is disputed whether the effects of hepatoprotectors could be repeated on animal models induced by different nanomaterials. Most studies focused on anti-inflammation strategy. Unfortunately, no reports have shown a critical factor in nanoparticle-induced inflammation, probably because there are too many imponderables, for example, sizes, doses, or subjects themselves, to distinguish one significant blocking target. Thus, it is practical to try compound hepatoprotection in clinical study and practice (Table 2).

Table 2

Comparison of different hepatoprotectors and their mechanism to reduce hepatotoxicity

Hepatoprotectors Mechanism Ref.
Melanin Anti-inflammation and activating antioxidant system [93]
α-Lipoic acid (ALA) Relieving nitrosative and inhabiting apoptosis [91]
Beetroot juice Anti-inflammation and attenuate ROS, activating the antioxidant system [92]

6.2 Ultrasound-assisted strategy

The ultrasound cavitation effects create pores between cells, which means improved vascular permeability and, thus, effective nanodrug transportation and fewer side effects [94]. Ultrasound-induced transient opening of the BBB is of great significance for nanoparticles to reach the central nervous systems and target lesions. Temozolomide (TMZ), a clinical first-line glioma chemotherapy drug, can be loaded in a zirconium-based frame, which collapses under ultrasonic stimulation due to low-frequency oscillations and cavitation effect [95]. Ultrasound can be combined with other strategies to further improve efficacy and alleviate hepatotoxicity. Nanoparticles modified with angiopep-2 peptide, a ligand targeting LRP1 (low-density lipoprotein receptor-related protein 1), which is highly expressed in tumors, achieved glioma-specific delivery in mice, but nanoparticles remain in the liver [96]. Further attempts included a nanodrug for luminescence imaging. Its hollow acoustic-sensitive TiO2 shell produced ROS for controlled drug release. It also encapsulates an immune checkpoint inhibitor (anti‐PD‐1 antibody) for glioma immunosuppression and paclitaxel. In vivo, liver luminescence images show fewer residues in the livers of C57 mice using ultrasound compared to those not using ultrasound [97]. Compared with photodynamic therapy and intervention techniques, ultrasound is non-invasive, focusable, and more penetrating, which also makes it difficult to handle ultrasound-induced bleeding. Whether ultrasound irradiation does not influence molecular structural stability of loading cannot be neglected (Figure 6) [98,99].

Figure 6 Schematic illustration of hollow TiO2 covered persistent luminescent nanosensitizer for ultrasound amplified chemo/immuno GBM therapy. (a) Composition of ZGO@TiO2@APL. “A” represents anti‐PD‐1 antibody, “L” represents liposome, and “P” represents PTX in the abbreviation “ALP”. (b) BBB penetration process of ZGO@TiO2@APL‐NEs. ZGO@TiO2@APL was loaded by neutrophils to form ZGO@TiO2@APL‐NEs in vitro. The injected ZGO@TiO2@APL‐NEs could be attracted by the inflammation in GBM to traverse the BBB. (c) Ultrasound-triggered drug release from ZGO@TiO2@APL‐NEs for GBM therapy. Activated by ultrasound, ROS was generated from ZGO@TiO2@ALP to break up liposome coverage for PTX, and an anti‐PD‐1 antibody was released to kill the tumor and induce local inflammation, which in turn attracted more ZGO@TiO2@ALP‐NEs to GBM sites for sustained therapy [97]. Reproduced with permission from the study of Li et al. [97]. Copyright 2021, Advanced Science, published by Wiley-VCH GmbH.
Figure 6

Schematic illustration of hollow TiO2 covered persistent luminescent nanosensitizer for ultrasound amplified chemo/immuno GBM therapy. (a) Composition of ZGO@TiO2@APL. “A” represents anti‐PD‐1 antibody, “L” represents liposome, and “P” represents PTX in the abbreviation “ALP”. (b) BBB penetration process of ZGO@TiO2@APL‐NEs. ZGO@TiO2@APL was loaded by neutrophils to form ZGO@TiO2@APL‐NEs in vitro. The injected ZGO@TiO2@APL‐NEs could be attracted by the inflammation in GBM to traverse the BBB. (c) Ultrasound-triggered drug release from ZGO@TiO2@APL‐NEs for GBM therapy. Activated by ultrasound, ROS was generated from ZGO@TiO2@ALP to break up liposome coverage for PTX, and an anti‐PD‐1 antibody was released to kill the tumor and induce local inflammation, which in turn attracted more ZGO@TiO2@ALP‐NEs to GBM sites for sustained therapy [97]. Reproduced with permission from the study of Li et al. [97]. Copyright 2021, Advanced Science, published by Wiley-VCH GmbH.

7 Conclusions and discussion

In this article, we discuss innovative ways to reduce liver damage caused by nanoparticles. Hydrogel and lipids are recommended for their high degree of biocompatibility. There are also more niche options, such as gelatin-based nanoparticles for brain medication delivery. Surface modification, bioinspired nanotechnology, and techniques like cell hijacking can be used to avoid liver uptake and achieve targeted medication distribution. Transient reduction of Kupffer cells reduces nanoparticle accumulation in the liver despite safety concerns. Hepatoprotective agents have unique pharmacological effects that help to reduce hepatotoxicity. Ultrasound, for example, can be used to aid nanoparticles in infiltrating lesions and to regulate the release of loads contained inside the nanoparticles.

Our knowledge about nanoparticle-induced damage is still limited, and few common features could cover most pathological processes. It seems that a special type of nanoparticle causes similar liver injury. Therefore, toxicological research focusing on FDA-approved carriers or nanoparticles of clinical translational value should be encouraged. Most studies have determined liver health only by testing for AST, ALA, and morphology. To thoroughly examine all potential alterations at the molecular level, it is advisable to provide evidence from protein mass spectrometry, RNA sequence, or gene sequencing. Second, studies on the long-term effects of nanoparticle-induced liver injury are lacking. However, cancer and AIDS treatment require long-term, often lifetime, care. Therefore, it is crucial to study the long-term effects of routinely used nanoparticles on the liver. In order to guide clinical therapy, we need more information to demonstrate a quantifiable link between targeted drug delivery and additional adjunctive techniques (e.g., ultrasonography) and their indirect hepatoprotective effects.

There is a need to investigate some overarching therapy strategies for acute liver damage caused by nanoparticles for usage in clinical settings. The contradiction between the anti-tumor effect of ROS and its toxicity cannot be ignored. In order to maximize the protective effects on the liver, it may be necessary to combine several approaches.

In the future, 3D liver models may be a better option for in vitro assessment of hepatotoxicity [100–102]. In addition, it may be possible to develop small molecules or monoclonal antibodies against receptors such as DR5 or to inactivate Kupffer cells. Efforts to reduce the costs of cell membrane coating nanotechnology and materials are significant for clinical transformation. The development of wearable (ultrasound) devices could also assist in the long-term control of nanodrugs to a great extent [103].

# These authors contributed equally to this work and should be considered first co-authors.

  1. Funding information: This work was supported by The Science and Technology Projects of Xiamen Municipal Bureau of Science and Technology (Grant Nos 3502Z20194042 and 2020J02063), Open Research Fund of Key Laboratory of Nanomedical Technology of Fujian Medical University (Grant No. 2022KLNT201), the Science Foundation of Fujian Province (2022J01019), Natural Science Foundation of Guangxi (2023GXNSFAA026023), Central Government Guided Local Science and Technology Development Fund Projects (2023ZYZX1090), National Natural Science Foundation of China (82360360), and National Natural Science Foundation of China (Grant No. 8200011769).

  2. Author contributions: T.C.G., M.D.W., Y.L.Z., S.J.M., H.X.L., and Z.X.W. participated in the organization, writing and editing of this manuscript. S.B.L., L.Z., and J.W.H. assisted in the editorial process. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Conflict of interest: The authors state no conflict of interest.

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Received: 2023-10-16
Revised: 2024-05-22
Accepted: 2024-07-11
Published Online: 2024-08-06

© 2024 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

Articles in the same Issue

  1. Research Articles
  2. Tension buckling and postbuckling of nanocomposite laminated plates with in-plane negative Poisson’s ratio
  3. Polyvinylpyrrolidone-stabilised gold nanoparticle coatings inhibit blood protein adsorption
  4. Energy and mass transmission through hybrid nanofluid flow passing over a spinning sphere with magnetic effect and heat source/sink
  5. Surface treatment with nano-silica and magnesium potassium phosphate cement co-action for enhancing recycled aggregate concrete
  6. Numerical investigation of thermal radiation with entropy generation effects in hybrid nanofluid flow over a shrinking/stretching sheet
  7. Enhancing the performance of thermal energy storage by adding nano-particles with paraffin phase change materials
  8. Using nano-CaCO3 and ceramic tile waste to design low-carbon ultra high performance concrete
  9. Numerical analysis of thermophoretic particle deposition in a magneto-Marangoni convective dusty tangent hyperbolic nanofluid flow – Thermal and magnetic features
  10. Dual numerical solutions of Casson SA–hybrid nanofluid toward a stagnation point flow over stretching/shrinking cylinder
  11. Single flake homo p–n diode of MoTe2 enabled by oxygen plasma doping
  12. Electrostatic self-assembly effect of Fe3O4 nanoparticles on performance of carbon nanotubes in cement-based materials
  13. Multi-scale alignment to buried atom-scale devices using Kelvin probe force microscopy
  14. Antibacterial, mechanical, and dielectric properties of hydroxyapatite cordierite/zirconia porous nanocomposites for use in bone tissue engineering applications
  15. Time-dependent Darcy–Forchheimer flow of Casson hybrid nanofluid comprising the CNTs through a Riga plate with nonlinear thermal radiation and viscous dissipation
  16. Durability prediction of geopolymer mortar reinforced with nanoparticles and PVA fiber using particle swarm optimized BP neural network
  17. Utilization of zein nano-based system for promoting antibiofilm and anti-virulence activities of curcumin against Pseudomonas aeruginosa
  18. Antibacterial effect of novel dental resin composites containing rod-like zinc oxide
  19. An extended model to assess Jeffery–Hamel blood flow through arteries with iron-oxide (Fe2O3) nanoparticles and melting effects: Entropy optimization analysis
  20. Comparative study of copper nanoparticles over radially stretching sheet with water and silicone oil
  21. Cementitious composites modified by nanocarbon fillers with cooperation effect possessing excellent self-sensing properties
  22. Confinement size effect on dielectric properties, antimicrobial activity, and recycling of TiO2 quantum dots via photodegradation processes of Congo red dye and real industrial textile wastewater
  23. Biogenic silver nanoparticles of Moringa oleifera leaf extract: Characterization and photocatalytic application
  24. Novel integrated structure and function of Mg–Gd neutron shielding materials
  25. Impact of multiple slips on thermally radiative peristaltic transport of Sisko nanofluid with double diffusion convection, viscous dissipation, and induced magnetic field
  26. Magnetized water-based hybrid nanofluid flow over an exponentially stretching sheet with thermal convective and mass flux conditions: HAM solution
  27. A numerical investigation of the two-dimensional magnetohydrodynamic water-based hybrid nanofluid flow composed of Fe3O4 and Au nanoparticles over a heated surface
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  30. Polymer nanocomposite for protecting photovoltaic cells from solar ultraviolet in space
  31. Study on the mechanical properties and microstructure of recycled concrete reinforced with basalt fibers and nano-silica in early low-temperature environments
  32. Synergistic effect of carbon nanotubes and polyvinyl alcohol on the mechanical performance and microstructure of cement mortar
  33. CFD analysis of paraffin-based hybrid (Co–Au) and trihybrid (Co–Au–ZrO2) nanofluid flow through a porous medium
  34. Forced convective tangent hyperbolic nanofluid flow subject to heat source/sink and Lorentz force over a permeable wedge: Numerical exploration
  35. Physiochemical and electrical activities of nano copper oxides synthesised via hydrothermal method utilising natural reduction agents for solar cell application
  36. A homotopic analysis of the blood-based bioconvection Carreau–Yasuda hybrid nanofluid flow over a stretching sheet with convective conditions
  37. In situ synthesis of reduced graphene oxide/SnIn4S8 nanocomposites with enhanced photocatalytic performance for pollutant degradation
  38. A coarse-grained Poisson–Nernst–Planck model for polyelectrolyte-modified nanofluidic diodes
  39. A numerical investigation of the magnetized water-based hybrid nanofluid flow over an extending sheet with a convective condition: Active and passive controls of nanoparticles
  40. The LyP-1 cyclic peptide modified mesoporous polydopamine nanospheres for targeted delivery of triptolide regulate the macrophage repolarization in atherosclerosis
  41. Synergistic effect of hydroxyapatite-magnetite nanocomposites in magnetic hyperthermia for bone cancer treatment
  42. The significance of quadratic thermal radiative scrutinization of a nanofluid flow across a microchannel with thermophoretic particle deposition effects
  43. Ferromagnetic effect on Casson nanofluid flow and transport phenomena across a bi-directional Riga sensor device: Darcy–Forchheimer model
  44. Performance of carbon nanomaterials incorporated with concrete exposed to high temperature
  45. Multicriteria-based optimization of roller compacted concrete pavement containing crumb rubber and nano-silica
  46. Revisiting hydrotalcite synthesis: Efficient combined mechanochemical/coprecipitation synthesis to design advanced tunable basic catalysts
  47. Exploration of irreversibility process and thermal energy of a tetra hybrid radiative binary nanofluid focusing on solar implementations
  48. Effect of graphene oxide on the properties of ternary limestone clay cement paste
  49. Improved mechanical properties of graphene-modified basalt fibre–epoxy composites
  50. Sodium titanate nanostructured modified by green synthesis of iron oxide for highly efficient photodegradation of dye contaminants
  51. Green synthesis of Vitis vinifera extract-appended magnesium oxide NPs for biomedical applications
  52. Differential study on the thermal–physical properties of metal and its oxide nanoparticle-formed nanofluids: Molecular dynamics simulation investigation of argon-based nanofluids
  53. Heat convection and irreversibility of magneto-micropolar hybrid nanofluids within a porous hexagonal-shaped enclosure having heated obstacle
  54. Numerical simulation and optimization of biological nanocomposite system for enhanced oil recovery
  55. Laser ablation and chemical vapor deposition to prepare a nanostructured PPy layer on the Ti surface
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  57. Linear and nonlinear optical studies on successfully mixed vanadium oxide and zinc oxide nanoparticles synthesized by sol–gel technique
  58. Analytical investigation of convective phenomena with nonlinearity characteristics in nanostratified liquid film above an inclined extended sheet
  59. Optimization method for low-velocity impact identification in nanocomposite using genetic algorithm
  60. Analyzing the 3D-MHD flow of a sodium alginate-based nanofluid flow containing alumina nanoparticles over a bi-directional extending sheet using variable porous medium and slip conditions
  61. A comprehensive study of laser irradiated hydrothermally synthesized 2D layered heterostructure V2O5(1−x)MoS2(x) (X = 1–5%) nanocomposites for photocatalytic application
  62. Computational analysis of water-based silver, copper, and alumina hybrid nanoparticles over a stretchable sheet embedded in a porous medium with thermophoretic particle deposition effects
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  68. Effect of annealing time on bending performance and microstructure of C19400 alloy strip
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  70. Electrospinning of MNZ/PLGA/SF nanofibers for periodontitis
  71. Photocatalytic degradation of methylene blue by Nd-doped titanium dioxide thin films
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  76. Advancing sustainable agriculture: Metal-doped urea–hydroxyapatite hybrid nanofertilizer for agro-industry
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https://doi.org/10.1515/ntrev-2024-0074
Keywords for this article
nanomaterial; hepatotoxicity; liver injury
Creative Commons
BY 4.0

Articles in the same Issue

  1. Research Articles
  2. Tension buckling and postbuckling of nanocomposite laminated plates with in-plane negative Poisson’s ratio
  3. Polyvinylpyrrolidone-stabilised gold nanoparticle coatings inhibit blood protein adsorption
  4. Energy and mass transmission through hybrid nanofluid flow passing over a spinning sphere with magnetic effect and heat source/sink
  5. Surface treatment with nano-silica and magnesium potassium phosphate cement co-action for enhancing recycled aggregate concrete
  6. Numerical investigation of thermal radiation with entropy generation effects in hybrid nanofluid flow over a shrinking/stretching sheet
  7. Enhancing the performance of thermal energy storage by adding nano-particles with paraffin phase change materials
  8. Using nano-CaCO3 and ceramic tile waste to design low-carbon ultra high performance concrete
  9. Numerical analysis of thermophoretic particle deposition in a magneto-Marangoni convective dusty tangent hyperbolic nanofluid flow – Thermal and magnetic features
  10. Dual numerical solutions of Casson SA–hybrid nanofluid toward a stagnation point flow over stretching/shrinking cylinder
  11. Single flake homo p–n diode of MoTe2 enabled by oxygen plasma doping
  12. Electrostatic self-assembly effect of Fe3O4 nanoparticles on performance of carbon nanotubes in cement-based materials
  13. Multi-scale alignment to buried atom-scale devices using Kelvin probe force microscopy
  14. Antibacterial, mechanical, and dielectric properties of hydroxyapatite cordierite/zirconia porous nanocomposites for use in bone tissue engineering applications
  15. Time-dependent Darcy–Forchheimer flow of Casson hybrid nanofluid comprising the CNTs through a Riga plate with nonlinear thermal radiation and viscous dissipation
  16. Durability prediction of geopolymer mortar reinforced with nanoparticles and PVA fiber using particle swarm optimized BP neural network
  17. Utilization of zein nano-based system for promoting antibiofilm and anti-virulence activities of curcumin against Pseudomonas aeruginosa
  18. Antibacterial effect of novel dental resin composites containing rod-like zinc oxide
  19. An extended model to assess Jeffery–Hamel blood flow through arteries with iron-oxide (Fe2O3) nanoparticles and melting effects: Entropy optimization analysis
  20. Comparative study of copper nanoparticles over radially stretching sheet with water and silicone oil
  21. Cementitious composites modified by nanocarbon fillers with cooperation effect possessing excellent self-sensing properties
  22. Confinement size effect on dielectric properties, antimicrobial activity, and recycling of TiO2 quantum dots via photodegradation processes of Congo red dye and real industrial textile wastewater
  23. Biogenic silver nanoparticles of Moringa oleifera leaf extract: Characterization and photocatalytic application
  24. Novel integrated structure and function of Mg–Gd neutron shielding materials
  25. Impact of multiple slips on thermally radiative peristaltic transport of Sisko nanofluid with double diffusion convection, viscous dissipation, and induced magnetic field
  26. Magnetized water-based hybrid nanofluid flow over an exponentially stretching sheet with thermal convective and mass flux conditions: HAM solution
  27. A numerical investigation of the two-dimensional magnetohydrodynamic water-based hybrid nanofluid flow composed of Fe3O4 and Au nanoparticles over a heated surface
  28. Development and modeling of an ultra-robust TPU-MWCNT foam with high flexibility and compressibility
  29. Effects of nanofillers on the physical, mechanical, and tribological behavior of carbon/kenaf fiber–reinforced phenolic composites
  30. Polymer nanocomposite for protecting photovoltaic cells from solar ultraviolet in space
  31. Study on the mechanical properties and microstructure of recycled concrete reinforced with basalt fibers and nano-silica in early low-temperature environments
  32. Synergistic effect of carbon nanotubes and polyvinyl alcohol on the mechanical performance and microstructure of cement mortar
  33. CFD analysis of paraffin-based hybrid (Co–Au) and trihybrid (Co–Au–ZrO2) nanofluid flow through a porous medium
  34. Forced convective tangent hyperbolic nanofluid flow subject to heat source/sink and Lorentz force over a permeable wedge: Numerical exploration
  35. Physiochemical and electrical activities of nano copper oxides synthesised via hydrothermal method utilising natural reduction agents for solar cell application
  36. A homotopic analysis of the blood-based bioconvection Carreau–Yasuda hybrid nanofluid flow over a stretching sheet with convective conditions
  37. In situ synthesis of reduced graphene oxide/SnIn4S8 nanocomposites with enhanced photocatalytic performance for pollutant degradation
  38. A coarse-grained Poisson–Nernst–Planck model for polyelectrolyte-modified nanofluidic diodes
  39. A numerical investigation of the magnetized water-based hybrid nanofluid flow over an extending sheet with a convective condition: Active and passive controls of nanoparticles
  40. The LyP-1 cyclic peptide modified mesoporous polydopamine nanospheres for targeted delivery of triptolide regulate the macrophage repolarization in atherosclerosis
  41. Synergistic effect of hydroxyapatite-magnetite nanocomposites in magnetic hyperthermia for bone cancer treatment
  42. The significance of quadratic thermal radiative scrutinization of a nanofluid flow across a microchannel with thermophoretic particle deposition effects
  43. Ferromagnetic effect on Casson nanofluid flow and transport phenomena across a bi-directional Riga sensor device: Darcy–Forchheimer model
  44. Performance of carbon nanomaterials incorporated with concrete exposed to high temperature
  45. Multicriteria-based optimization of roller compacted concrete pavement containing crumb rubber and nano-silica
  46. Revisiting hydrotalcite synthesis: Efficient combined mechanochemical/coprecipitation synthesis to design advanced tunable basic catalysts
  47. Exploration of irreversibility process and thermal energy of a tetra hybrid radiative binary nanofluid focusing on solar implementations
  48. Effect of graphene oxide on the properties of ternary limestone clay cement paste
  49. Improved mechanical properties of graphene-modified basalt fibre–epoxy composites
  50. Sodium titanate nanostructured modified by green synthesis of iron oxide for highly efficient photodegradation of dye contaminants
  51. Green synthesis of Vitis vinifera extract-appended magnesium oxide NPs for biomedical applications
  52. Differential study on the thermal–physical properties of metal and its oxide nanoparticle-formed nanofluids: Molecular dynamics simulation investigation of argon-based nanofluids
  53. Heat convection and irreversibility of magneto-micropolar hybrid nanofluids within a porous hexagonal-shaped enclosure having heated obstacle
  54. Numerical simulation and optimization of biological nanocomposite system for enhanced oil recovery
  55. Laser ablation and chemical vapor deposition to prepare a nanostructured PPy layer on the Ti surface
  56. Cilostazol niosomes-loaded transdermal gels: An in vitro and in vivo anti-aggregant and skin permeation activity investigations towards preparing an efficient nanoscale formulation
  57. Linear and nonlinear optical studies on successfully mixed vanadium oxide and zinc oxide nanoparticles synthesized by sol–gel technique
  58. Analytical investigation of convective phenomena with nonlinearity characteristics in nanostratified liquid film above an inclined extended sheet
  59. Optimization method for low-velocity impact identification in nanocomposite using genetic algorithm
  60. Analyzing the 3D-MHD flow of a sodium alginate-based nanofluid flow containing alumina nanoparticles over a bi-directional extending sheet using variable porous medium and slip conditions
  61. A comprehensive study of laser irradiated hydrothermally synthesized 2D layered heterostructure V2O5(1−x)MoS2(x) (X = 1–5%) nanocomposites for photocatalytic application
  62. Computational analysis of water-based silver, copper, and alumina hybrid nanoparticles over a stretchable sheet embedded in a porous medium with thermophoretic particle deposition effects
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  64. Effects of normal strain on pyramidal I and II 〈c + a〉 screw dislocation mobility and structure in single-crystal magnesium
  65. Computational study of cross-flow in entropy-optimized nanofluids
  66. Significance of nanoparticle aggregation for thermal transport over magnetized sensor surface
  67. A green and facile synthesis route of nanosize cupric oxide at room temperature
  68. Effect of annealing time on bending performance and microstructure of C19400 alloy strip
  69. Chitosan-based Mupirocin and Alkanna tinctoria extract nanoparticles for the management of burn wound: In vitro and in vivo characterization
  70. Electrospinning of MNZ/PLGA/SF nanofibers for periodontitis
  71. Photocatalytic degradation of methylene blue by Nd-doped titanium dioxide thin films
  72. Shell-core-structured electrospinning film with sequential anti-inflammatory and pro-neurogenic effects for peripheral nerve repairment
  73. Flow and heat transfer insights into a chemically reactive micropolar Williamson ternary hybrid nanofluid with cross-diffusion theory
  74. One-pot fabrication of open-spherical shapes based on the decoration of copper sulfide/poly-O-amino benzenethiol on copper oxide as a promising photocathode for hydrogen generation from the natural source of Red Sea water
  75. A penta-hybrid approach for modeling the nanofluid flow in a spatially dependent magnetic field
  76. Advancing sustainable agriculture: Metal-doped urea–hydroxyapatite hybrid nanofertilizer for agro-industry
  77. Utilizing Ziziphus spina-christi for eco-friendly synthesis of silver nanoparticles: Antimicrobial activity and promising application in wound healing
  78. Plant-mediated synthesis, characterization, and evaluation of a copper oxide/silicon dioxide nanocomposite by an antimicrobial study
  79. Effects of PVA fibers and nano-SiO2 on rheological properties of geopolymer mortar
  80. Investigating silver and alumina nanoparticles’ impact on fluid behavior over porous stretching surface
  81. Potential pharmaceutical applications and molecular docking study for green fabricated ZnO nanoparticles mediated Raphanus sativus: In vitro and in vivo study
  82. Effect of temperature and nanoparticle size on the interfacial layer thickness of TiO2–water nanofluids using molecular dynamics
  83. Characteristics of induced magnetic field on the time-dependent MHD nanofluid flow through parallel plates
  84. Flexural and vibration behaviours of novel covered CFRP composite joints with an MWCNT-modified adhesive
  85. Experimental research on mechanically and thermally activation of nano-kaolin to improve the properties of ultra-high-performance fiber-reinforced concrete
  86. Analysis of variable fluid properties for three-dimensional flow of ternary hybrid nanofluid on a stretching sheet with MHD effects
  87. Biodegradability of corn starch films containing nanocellulose fiber and thymol
  88. Toxicity assessment of copper oxide nanoparticles: In vivo study
  89. Some measures to enhance the energy output performances of triboelectric nanogenerators
  90. Reinforcement of graphene nanoplatelets on water uptake and thermomechanical behaviour of epoxy adhesive subjected to water ageing conditions
  91. Optimization of preparation parameters and testing verification of carbon nanotube suspensions used in concrete
  92. Max-phase Ti3SiC2 and diverse nanoparticle reinforcements for enhancement of the mechanical, dynamic, and microstructural properties of AA5083 aluminum alloy via FSP
  93. Advancing drug delivery: Neural network perspectives on nanoparticle-mediated treatments for cancerous tissues
  94. PEG-PLGA core–shell nanoparticles for the controlled delivery of picoplatin–hydroxypropyl β-cyclodextrin inclusion complex in triple-negative breast cancer: In vitro and in vivo study
  95. Conduction transportation from graphene to an insulative polymer medium: A novel approach for the conductivity of nanocomposites
  96. Review Articles
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  98. Overview of amorphous carbon memristor device, modeling, and applications for neuromorphic computing
  99. Advances in the synthesis of gold nanoclusters (AuNCs) of proteins extracted from nature
  100. A review of ternary polymer nanocomposites containing clay and calcium carbonate and their biomedical applications
  101. Recent advancements in polyoxometalate-functionalized fiber materials: A review
  102. Special contribution of atomic force microscopy in cell death research
  103. A comprehensive review of oral chitosan drug delivery systems: Applications for oral insulin delivery
  104. Cellular senescence and nanoparticle-based therapies: Current developments and perspectives
  105. Cyclodextrins-block copolymer drug delivery systems: From design and development to preclinical studies
  106. Micelle-based nanoparticles with stimuli-responsive properties for drug delivery
  107. Critical assessment of the thermal stability and degradation of chemically functionalized nanocellulose-based polymer nanocomposites
  108. Research progress in preparation technology of micro and nano titanium alloy powder
  109. Nanoformulations for lysozyme-based additives in animal feed: An alternative to fight antibiotic resistance spread
  110. Incorporation of organic photochromic molecules in mesoporous silica materials: Synthesis and applications
  111. A review on modeling of graphene and associated nanostructures reinforced concrete
  112. A review on strengthening mechanisms of carbon quantum dots-reinforced Cu-matrix nanocomposites
  113. Review on nanocellulose composites and CNFs assembled microfiber toward automotive applications
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  121. Twisto-photonics in two-dimensional materials: A comprehensive review
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  123. Recent process of using nanoparticles in the T cell-based immunometabolic therapy
  124. Future prospects of gold nanoclusters in hydrogen storage systems and sustainable environmental treatment applications
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  131. Structural performance of boards through nanoparticle reinforcement: An advance review
  132. Reinforcing mechanisms review of the graphene oxide on cement composites
  133. Seed regeneration aided by nanomaterials in a climate change scenario: A comprehensive review
  134. Surface-engineered quantum dot nanocomposites for neurodegenerative disorder remediation and avenue for neuroimaging
  135. Graphitic carbon nitride hybrid thin films for energy conversion: A mini-review on defect activation with different materials
  136. Nanoparticles and the treatment of hepatocellular carcinoma
  137. Special Issue on Advanced Nanomaterials and Composites for Energy Conversion and Storage - Part II
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  139. Recent progress in nanomaterials of battery energy storage: A patent landscape analysis, technology updates, and future prospects
  140. Special Issue on Advanced Nanomaterials for Carbon Capture, Environment and Utilization for Energy Sustainability - Part II
  141. Calcium-, magnesium-, and yttrium-doped lithium nickel phosphate nanomaterials as high-performance catalysts for electrochemical water oxidation reaction
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  143. Mesoporous silica-grafted deep eutectic solvent-based mixed matrix membranes for wastewater treatment: Synthesis and emerging pollutant removal performance
  144. Electrochemically prepared ultrathin two-dimensional graphitic nanosheets as cathodes for advanced Zn-based energy storage devices
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  146. Incorporating GO in PI matrix to advance nanocomposite coating: An enhancing strategy to prevent corrosion
  147. Synthesis, characterization, thermal stability, and application of microporous hyper cross-linked polyphosphazenes with naphthylamine group for CO2 uptake
  148. Engineering in ceramic albite morphology by the addition of additives: Carbon nanotubes and graphene oxide for energy applications
  149. Nanoscale synergy: Optimizing energy storage with SnO2 quantum dots on ZnO hexagonal prisms for advanced supercapacitors
  150. Aging assessment of silicone rubber materials under corona discharge accompanied by humidity and UV radiation
  151. Tuning structural and electrical properties of Co-precipitated and Cu-incorporated nickel ferrite for energy applications
  152. Sodium alginate-supported AgSr nanoparticles for catalytic degradation of malachite green and methyl orange in aqueous medium
  153. An environmentally greener and reusability approach for bioenergy production using Mallotus philippensis (Kamala) seed oil feedstock via phytonanotechnology
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  155. Mechanism exploration of ion-implanted epoxy on surface trap distribution: An approach to augment the vacuum flashover voltages
  156. Nanoscale engineering of semiconductor photocatalysts boosting charge separation for solar-driven H2 production: Recent advances and future perspective
  157. Excellent catalytic performance over reduced graphene-boosted novel nanoparticles for oxidative desulfurization of fuel oil
  158. Special Issue on Advances in Nanotechnology for Agriculture
  159. Deciphering the synergistic potential of mycogenic zinc oxide nanoparticles and bio-slurry formulation on phenology and physiology of Vigna radiata
  160. Nanomaterials: Cross-disciplinary applications in ornamental plants
  161. Special Issue on Catechol Based Nano and Microstructures
  162. Polydopamine films: Versatile but interface-dependent coatings
  163. In vitro anticancer activity of melanin-like nanoparticles for multimodal therapy of glioblastoma
  164. Poly-3,4-dihydroxybenzylidenhydrazine, a different analogue of polydopamine
  165. Chirality and self-assembly of structures derived from optically active 1,2-diaminocyclohexane and catecholamines
  166. Advancing resource sustainability with green photothermal materials: Insights from organic waste-derived and bioderived sources
  167. Bioinspired neuromelanin-like Pt(iv) polymeric nanoparticles for cancer treatment
  168. Special Issue on Implementing Nanotechnology for Smart Healthcare System
  169. Intelligent explainable optical sensing on Internet of nanorobots for disease detection
  170. Special Issue on Green Mono, Bi and Tri Metallic Nanoparticles for Biological and Environmental Applications
  171. Tracking success of interaction of green-synthesized Carbopol nanoemulgel (neomycin-decorated Ag/ZnO nanocomposite) with wound-based MDR bacteria
  172. Green synthesis of copper oxide nanoparticles using genus Inula and evaluation of biological therapeutics and environmental applications
  173. Biogenic fabrication and multifunctional therapeutic applications of silver nanoparticles synthesized from rose petal extract
  174. Metal oxides on the frontlines: Antimicrobial activity in plant-derived biometallic nanoparticles
  175. Controlling pore size during the synthesis of hydroxyapatite nanoparticles using CTAB by the sol–gel hydrothermal method and their biological activities
  176. Special Issue on State-of-Art Advanced Nanotechnology for Healthcare
  177. Applications of nanomedicine-integrated phototherapeutic agents in cancer theranostics: A comprehensive review of the current state of research
  178. Smart bionanomaterials for treatment and diagnosis of inflammatory bowel disease
  179. Beyond conventional therapy: Synthesis of multifunctional nanoparticles for rheumatoid arthritis therapy
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