Advances in organic–inorganic nanocomposites for cancer imaging and therapy

2.1.1 Organic-silica nanocomposites

Although most of the silica-based nanomaterials exhibit no diagnostic or therapeutic role, silica nanoparticles have shown great biocompatibility and biosafety, as well as no obvious toxicity to organisms. Therefore, silica nanoparticles can be loaded with various cargos to target tumors for cancer imaging and therapy through combining with organic materials or modifying surface [4,18]. Shi et al. reviewed a multifunctional theranostic nanoplatform: silica/organosilica cross-linked block copolymer micelles, in which different block copolymers, organosilanes, and cargos were incorporated to prepare diverse crosslinked block copolymer micelles with different properties and functions [19]. For example, conjugated fluorescent copolymers and superparamagnetic iron oxide nanoparticles were co-loaded inside silicas crosslinked F127 polyethylene oxide₁₀₆ (PEO₁₀₆)-b-polypropylene oxide₇₀-b-PEO₁₀₆ micelles to prepare a FL/T₂-weighted MR dual-mode imaging nanocomposite, which can effectively target tumor cells under the influence of an external magnetic field, and significantly improve the efficacy of FL/MR imaging. Furthermore, these organic-silica nanocomposites have also exhibited several advantages over the typical silica-based nanoparticles, including targeted drug delivery, microenvironmental stability, and preferable bio-imaging capabilities. However, the usage of non-biodegradable PEO and poly(acrylic acid)-based block copolymer as construction blocks limits the further application of these organic-silica nanocomposites, thus novel biodegradable block copolymers should be designed and prepared to improve their performance.

Simultaneously, Lu et al. designed an OX/IND-MSNPs nanosystem for the treatment of pancreatic ductal adenocarcinoma, in which IDO (immunosuppressive indoleamine 2,3-dioxy-genase) inhibitor indoximod (IND) was coupled with phospholipid to encapsulate oxaliplatin (OX) loaded in mesoporous silica nanoparticles (MSNPs) (Figure 2a). The dual delivery system of OX and IND induces immunogenic cell death of pancreatic ductal adenocarcinoma via an OX chemotherapy regimen, cooperating with IND interference on the IDO pathway to enhance immunogenic cell death. Through linking with a single chain phospholipid, the problem of poor water solubility and rapid blood elimination of IND were improved, as well as the biological distribution, retention, and pharmacokinetics of IND in tumor sites were enhanced (Figure 2b–d) [20]. Obviously, surface-functionalized silica can be taken as an excellent cargo carrier for cancer imaging and therapy.

Figure 2

Organic-silica nanocomposites for cancer treatment. (a) Schematic of mesoporous silica drug delivery system, which is encapsulated by a lipid containing a phospholipid-conjugated IND prodrug. (b) Biodistribution of optical imaging in vivo and in vitro. (c) Comparison of the cellular drug uptake between phospholipid-conjugated IND nanovesicles (IND-NV) and free IND. (d) Pharmacokinetic evaluation of OX/IND-MSNPs in situ of tumor-bearing mice. Free OX was the control. Adapted with permission from ref. [20], Copyright, 2017, Lu et al. (e) Diagram of the construction of Janus Gold Triangle-Mesoporous Silica (Janus MSNPs) and Schematic illustration of tumor therapy. (f) Tumor images. (g) Tumor growth curves. (h) Release behavior of TPZ from Janus NPs at pH 5.5 and pH 7.4. Adapted with permission from ref. [29], Copyright, 2019, American Chemical Society.

Moreover, silica coated with organic materials has also been prepared for targeting tumor and controlled release of cargos to realize cancer imaging and therapy. Fu et al. designed chitosan (CS) encapsulated hollow MSNPs, which is able to release benzoyl peroxide (BPO) in response to pH, and the released BPO could produce free radicals to regulate tumor cell apoptosis in tumor microenvironment, whereas only a few BPO is released into normal cells [21]. Similarly, Cheng and coworkers prepared a pH-responsive nanocarrier (MSNPs@PDA-TPGS) for releasing doxorubicin (DOX) through modifying polydopamine (PDA)-encapsulated MSNPs with d-a-tocopheryl polyethylene glycol 1000 succinate (TPGS) to produce this nanocarrier, which can enhance the chemotherapeutic effect of lung cancer with multidrug resistance (MDR). Theoretically, PDA was dissolved in tumor acidic microenvironment for DOX release, and the addition of TPGS suppressed the activities of P-glycoprotein, thus inhibiting P-glycoprotein mediated MDR in tumor cells, and further enhanced the cytotoxicity of DOX to tumor cells. Thereafter, the in vivo and ex vivo analyses further revealed that this nanocarrier exhibited excellent therapeutic effect on lung cancer with MDR, providing a referable strategy for treatment of tumor with MDR [22].

In addition to pH-responsive drug-controlled release nanocomposites, other organic materials (liposomes, dendrimer, and polymer) encapsulated porous silica-based nanoparticles are employed for controlled release of drugs in magnetothermal, photothermal, and near infrared response [23,24]. Exogenous response systems, such as near-infrared (NIR) and magnetocaloric response, are easier to control drug release than endogenous response systems, such as pH response. For instance, Zhao et al. designed polymer nanocapsules that can be degraded to release drugs in response to NIR light, and the capsules are composed of spherical silica micelles and a polymer that is electrostatically formed layer by layer on the micelle surface. During the preparation of polymer, up-down conversion nanoparticles (U/DCNPs) were introduced and Tm³⁺ was further doped into U/DCNPs, which can convert NIR photons into ultraviolet/visible photons. Subsequently, ultraviolet/visible sensitive azobenzene functional groups were introduced into the polymer to achieve near infrared photodegradation, which can be quickly removed from tumor tissue and the contained chemotherapy drugs were released within 1 h after degradation [24]. Simultaneously, Kong et al. combined with porous silica nanoparticles with giant liposomes to produce a biodegradable nano-in-micro platform that could be used in conjunction with DNA nanostructures, iron oxide nanoparticles, and gold nanorods (GNR) to accomplish magnetothermal and photothermal responsive release of drugs [23]. Because liposome encapsulation enhanced the cytocompatibility of the nanoplatform, which can easily enter the tumor cells and release DOX and other drugs under magnetothermal or photothermal response. Furthermore, the combination of DNA nanostructures and drugs exhibit stronger cytotoxicity on DOX-resistant tumor cells than drugs used alone, which demonstrated that DNA nanostructures might improve the cytotoxicity of DOX on DOX-resistant MCF-7 cells through inhibiting lysosomal acidification, resulting in the aggregation of the drug in tumor sites. Conclusively, these silica-based organic nanocomposites exhibit excellent biocompatibility and drug loading capacity, suggesting a potential strategy for controlled drug release used in cancer treatment.

Based on published reports, besides combining with organic nanomaterials for drug delivery, silica nanoparticles can also be combined with other nanomaterials for conferring the newly prepared nanocomposites with physical properties, such as magnetic, optical, and thermal properties that could be employed in cancer imaging and therapy [25,26,27,28,29]. Wang et al. designed and constructed a Janus golden triangle mesoporous silica nano-multifunctional platform for the liver cancer synergistic treatment with hypoxia activated chemotherapy, radiation, and PTT. This nanoplatform combined the surface of Janus golden triangle mesoporous silica nanoparticles (GT-MSNPs) with polyethylene glycol (PEG) coupled with FA, and the anoxic activated tirapazamine (TPZ) prodrug was loaded into mesoporous silica pores to produce an FA-GT-MSNPs@TPZ nanocomposite (Figure 2e) [29]. The subsequent results demonstrated that the PEG on the surface of the nanocomposites can be dissolved in the tumor acidic environment and a considerable quantity of TPZ were released after FA-mediated endocytosis (Figure 2h), and DNA-damaging free radicals were produced in an anoxic environment. Furthermore, the existence of the golden triangle endows the nanocomposite with photothermal property and radiosensitivity, contributing to TPZ-induced chemotherapy and enhanced cytotoxicity of nanoplatform to hepatoma cells (Figure 2f and g).

Additionally, Seo and coworkers successfully prepared silica encapsulated GNR loaded with methylene blue (MB) core-shell nanoparticles (MB-GNR@SiO₂), which can be employed for tumor imaging and photothermal, photodynamic dual-mode tumor therapy [27]. Then, they PEGylated GNR@SiO₂ nanoparticles using poly(ethylene glycol) methyl ether thiol to improve the nanoparticle’s stability. Because of the excellent plasmonic properties of GNR at NIR light, the embedded MB molecules can exhibit NIR-induced surface-enhanced Raman scattering (SERS) properties, and are capable of detecting both single and aggregated cancer cells at cellular level, which provide support for early diagnosis of cancer. And the nanocomposite has a photothermal and photodynamic dual mode cancer synergistic treatment generated by NIR light. This empirical evidence suggests that MB-GNR@SiO₂ nanoparticles have promising potential in cancer theranostics.

As a drug carrier, MSNPs exhibit high stability and drug loading capacity, as well as uniform structure. The further modification with tumor recognition molecules and gatekeeper molecules could remarkably improve the efficacy of tumor therapy and amelioration of the damage to normal tissue. Distinguished from other types of metal and non-metal carriers with cytotoxicity, MSNPs are generally considered to be relatively safe by Food and Drug Administration and is recognized as a more ideal therapeutic nanoplatform. MSNPs show their potential in clinical applications, but comprehensive and precise mechanism studies on the degradation and pharmacokinetics of MSNPs are still required. Promisingly, the introduction of biodegradable groups (such as thioether) into the MSNPs framework to prepare biodegradable organosilica nanoparticles have attracted attention of a large number of researchers at present, promoting the clinical application of MSNPs.

2.1.2 Organic-carbon nanomaterials

Carbon nanomaterials are multiple types of nanomaterials based on carbon elemental, such as graphene, fullerenes, CNTs and carbon QDs, and various carbon nanomaterials and their derived complexes have been widely studied and applied in cancer imaging and therapy [2]. These carbon nanomaterials exhibit excellent biocompatibility after covalent and non-covalent modifications. Covalent modification is mainly to anchor the functional groups to its surface, such as hydroxyl groups, carboxyl groups, and amino groups, which further conjugate with biopolymers. The non-covalent modification is mainly to bind the amphiphilic molecules similar to phospholipids on carbon nanomaterials. Moreover, because of its high specific surface area, huge attention has been paid on taking carbon nanomaterials as the carriers of imaging probes and antitumor drugs for cancer imaging and treatment [7,30,31,32,33,34,35]. For example, Zheng et al. prepared a nanocarrier (anti-HER2-RGO-PLL), which is a poly-l-lysine (PLL)-modified reduced graphene oxide (RGO) coupled with an anti-HER2 antibody, and this nanocarrier is capable of efficiently delivering DOX into the nuclei of HER2-overexpressed tumor cells [36]. PLL, a cationic polymer that makes the nanocarrier positively charged for enhancing their interaction between the nanocarrier and the negatively charged cell membrane, further promotes the efficient endocytosis of nanocarriers in tumor cells. While the conjugated anti-HER2 antibody can improve the endocytosis of nanocarriers by HER2-overexpressed tumor cells, the anti-tumor effect of anti-HER2-RGO-PLL/DOX nanocarriers was seven times more than that of RGO-PLL/DOX nanocarriers, which is likely to be contributed by the increased concentration of DOX in the tumor cells after enhancing anti-HER2 antibody mediated endocytosis.

Furthermore, Miao and coworkers prepared cholesterol-hyaluronic acid encapsulated RGO (CHA-RGO) nanocarriers for targeting delivery of anticancer drugs [34]. The subsequent results demonstrated that under physiological conditions, CHA-RGO exhibited superior colloidal stability and biosafety when compared with RGO alone. Further, CHA encapsulation dramatically increased the DOX-loading capacity of RGO, and promoted the aggregation of DOX at tumors, contributing to the enhanced endocytosis of DOX by CD44 overexpressed kb cells and improved anti-tumor effects in vivo.

Distinguished from silica-based nanomaterials, carbon-based nanomaterials exhibit unique optical and thermal properties beside of excellent biocompatibility and drugs-loading capacity. Therefore, carbon nanomaterials can be employed not only as carrier of drugs and imaging probes, but also for cancer PTT and PDT [37,38,39,40,41,42,43]. For instance, Guo and coworkers prepared CS coated graphene carbon nanocages (GCNCs) loaded with 5-fluorouracil (Fu) (CS-GCNCs/5-Fu), which is used for the photothermal-chemical synergistic treatment of tumors with 808 nm laser and microwave co-radiation releasing 5-Fu [42] (Figure 3a). The subsequent results revealed that after being encapsulated into CS, the carbon nano-cages-induced cell cycle defects were reduced, contributing to the minimization of nano-cages-induced cytotoxicity (Figure 3d and e). Simultaneously, as a result of the CS encapsulation, the release of 5-Fu from the nanomaterials was significantly decelerated but accelerated at 808 nm laser and microwave co-radiation (Figure 3b and c). Furthermore, the CS-GCNCs/5-Fu exhibits severe toxicity on tumor cells due to the enhanced thermal therapy of GCNC triggered by microwave, laser irradiation, and the synergistic chemotherapy of 5-Fu. Consequently, this study paved the way for the application of GCNC-based biological nanomaterials in photothermal-chemical synergistic cancer treatment with microwave radiation.

Figure 3

Organic-carbon nanocomposites for cancer imaging and therapy. (a) Schematic of CS-coated GCNCs for cancer treatment. (b) Comparison of the release rates of 5Fu from different nanoparticles. (c) Both laser and microwave promote the release of 5Fu. (d) The effect of nanomaterials on cell cycle distribution. (e) Cell viability examination after co-incubation with different groups. Adapted with permission from ref. [42], Copyright, 2019, Acta Materialia Inc. (f) Synthetic method of MWCNT-Gd@PDA-PEG and its imaging-guided therapy for metastatic lymph nodes (LNs). (g) Dual-mode imaging of regional LNs. MR imaging of popliteal, sciatic, and iliac common LNs in control group (1–3) and 2 h after MWCNT-Gd@PDA-PEG injection (4–6), images of popliteal, sciatic, and iliac common LNs without injection of MWCNT-Gd@PDA-PEG (10–12), and 2 h after injection of MWCNT-Gd@PDA-PEG (7–9). (h) The mice photographs after the tumor PTT. (A and B were treated with MWCNT-Gd@PDA-PEG with and without NIR light, respectively; C and D were treated with normal saline (NS) with or without NIR light). (i) Relative tumor volume curves after different treatments. Adapted with permission from ref. [48], Copyright, 2016, Elsevier Ltd.

By encapsulating cucurbit[7]uril conjugated graphene oxide with adamantane-labeled HA (ADA-HA), Ding et al. prepared supramolecular nanomaterials for OX, banoxantrone dihydrochloride (AQ4N, a hypoxia-responsive prodrug), chlorin e6 co-loaded tumor-targeted delivery, and multimodal cancer therapy [37]. The encapsulation of ADA-HA increased the stability and biocompatibility of the nanomaterials, being capable of delivering medicines to CD44 overexpressed cancer cells. When the nanomaterials were targeted to tumors, the heat generated by the photothermal action of nano graphene oxide under NIR irradiation might not only kill the tumor cells but also trigger the release of OX for chemotherapy. Similarly, chlorin e6-induced photodynamic effect consumes oxygen and exacerbates hypoxia in the tumor, converting non-toxic AQ4N into toxic AQ4 and further killing tumor cells. Furthermore, in vivo and ex vivo analysis have also confirmed the photothermal, photodynamic, and synergistic chemotherapeutic effects of the nanomaterials in cancer therapy, providing a novel organic–inorganic nanocomposite for multiple cancer therapies.

Furthermore, nanocomposites prepared from organic-carbon nanomaterials with other nanomaterials have also been investigated and employed in cancer imaging and therapy [44,45,46,47,48]. Fu group prepared PEG and PDA encapsulated gadolinium (Gd)-loaded MWCNTs (MWCNTs-Gd@PDA-PEG) for MR and color imaging guided PTT, contributing to eliminate the primary tumor and tumor cells in metastatic regional lymph node (RLN) (Figure 3f) [48]. PDA and PEG encapsulation significantly prevented Gd from leaking from MWCNTs, enhancing the biocompatibility of the nanocomposites. The subsequent analysis in vitro and in vivo indicated that the nanocomposite can be used to trace the tumor cells in RLN via T1-weighted MR imaging and dye dual-mode (Figure 3g), as well as guide NIR PTT to eradicate the tumor cells in primary and metastatic RLN (Figure 3h and i). Simultaneously, MWCNTs-Gd@PDA-PEG exhibit severe toxicity on tumor cells, which is superior to surgery in terms of speed and effectiveness. However, no in-depth study and data on the toxicity and biosafety of this nanocomposite in vivo are reported, which play an indispensable role for their clinical application.

Additionally, Wang et al. prepared porous carbon hybrid nanozyme (CuCo(O)/GOx@PCNs) doped with copper cobalt oxide (CuCo(O)) based on double ZIF-8/ZIF67, and loaded glucose oxidase (GOx) for immunotherapy/enhanced starvation/PTT of cancer [49]. In another interesting study, Yan and coworkers prepared novel iron oxychloride nanosheets (FeOCl@PEG@CDs) coated with PEG and inorganic CDs for CDT/PTT antibacterial therapy [50]. The subsequent analysis demonstrated that FeOCl@PEG@CDs could catalyze H₂O₂ to produce hydroxyl radical (˙OH) and trigger bacterial mortality, and NIR irradiation induces a substantial photothermal effect (local temperature can reach to 52°C), significantly boosting their antibacterial activity. Based on the performance of FeOCl@PEG@CDs in antibacterial therapy, it is reasonable to postulate that this nanocomposite is promising to be applied in cancer therapy. On the one hand, tumor cells contain H₂O₂, which can be catalyzed by the nanocomposite to produce ˙OH for tumor CDT, on the other hand, the heat generated by photothermal effect of the nanocomposite under NIR is beneficial to pyrolyze the tumor cells. However, the safety of carbon nanomaterials is a major obstacle to their clinical application, such as high liver uptake and low body clearance, which are the critical problems that need to be addressed. Therefore, the development of functionalized carbon nanomaterials with excellent tumor targeting capacity and in vivo degradability may be the further research focus.

2.1.3 Organic-QDs nanocomposites

QDs are likely the most ideal fluorescent imaging material due to their superior optical characteristics and small particle size. To satisfy the requirements of clinical tumor treatment and achieve the optimal imaging results, QDs must be water soluble and biocompatible, as well as exhibit high quantum yield and adjustable emission wavelength. However, the hydrophobic surface of QDs results in low water solubility, limiting its direct application in biological environments [51]. Therefore, the researchers modified the surface of QDs with hydrophilic organic compounds to increase the hydrophilicity of QDs, conferring the organic-modified QDs with excellent water solubility, FL intensity, and stability, attracting extensive attention in cancer imaging [52,53,54,55]. For example, Pang group designed a second near-infrared (NIR II) fluorescent probe, a mixture of Ag₂Te QDs and poly(lactic-co-glycolic acid) encapsulated in cell membrane of 4T1 cells for in vivo imaging, and the subsequent analysis demonstrated that the probe greatly improved their FL intensity (about 60 times that of free Ag₂Te QDs) and FL stability (about 97% after 1 h of laser irradiation) [52]. Simultaneously, the cell membrane of 4T1 cells enables the fluorescent probe to target the tumors, and promote the probe to effectively aggregate in tumor tissues ((31 ± 2)% of the injected dose per gram of tumor), exhibiting a high tumor to normal tissue aggregation ratio (13.3 ± 0.7).

Moreover, Jeong et al. synthesized polymer encapsulated size-controllable PbS/CdS core-shell QDs (PQDs) for in vivo FL imaging under NIR II, and the synthesized PQDs exhibit a variety of emission wavelengths through regulating the size of the PbS core and the thickness of the CdS shell [56]. This PQDs not only possess high FL stability by emitting stable FL for one week in biological environment, but also exhibits low cytotoxicity (cell viability >90% after co-incubation) by coupling FA to PQDs to form FA-PQDs, which can improve the aggregation of PQDs in tumors by actively targeting folate receptor overexpressed tumor cells.

Besides attracting increasing attention in tumor imaging, organically modified QDs have also been applied in cancer therapy, and the preparation of QDs with both imaging and therapeutic functions exhibit promising applicable potential, mainly including imaging-guided drug delivery [57,58,59,60], phototherapy [61,62,63,64,65,66], and surgery therapy [67]. For drug delivery, Wang group prepared the Ald/DOX@PEG-Ag₂S nanosystem for osteolysis inhibition and chemotherapy in an orthotopic bone tumor model (Figure 4a) [57]. Alendronate (Ald) is attached to the surface of the PEG-Ag₂S QD to prevent osteolysis through effectively promoting the targeted aggregation of Ald/DOX@PEG-Ag₂S in bone tissues (Figure 4b and d). Further, the nanosystem exhibits a longer circulation time and avoids phagocytosis by macrophages after surface functionalization with PEG, increasing targeted efficiency. Meanwhile, targeted release of DOX in the tumor acidic environment for bone tumor chemotherapy can reduce toxicity to normal bone tissues (Figure 4c).

Figure 4

Organic-QDs nanocomposites and their therapeutic applications. (a) Diagram of Ag₂S QDs nanocomposites for bone cancer treatment. (b) NIR-II FL images of mice at 12 h post-injection with different treatments. (c) Cumulative release of DOX from Ald/DOX@Ag₂S under different pH values. (d) Staining of the dissected tibias of tumor-bearing mice after treatment. Necrotic debris from tumor cells is indicated by the black arrows. Apoptotic tumor cells are indicated by red arrows. Adapted with permission from ref. [57], Copyright, 2017, WILEY-VCH. (e) Diagram of BPQDs for cancer therapy. (f) The top views of 3D PT-OCT images of tumor regions after intravenous injection with BPQD/Cys-8E nanoparticles for 0, 8, 24, and 48 h were reconstructed from 500 sequential B-scans (scale bars: 1 mm). (g) Cumulative release of PTX from BPQD/Cys-8E/PTX quantified by high-performance liquid chromatography. (h) Photographs of the tumors after 18 days with different treatments. (Group I: control, II: control + laser, III: PTX, IV: BPQDs, V: BPQD/Cys-8E + laser, VI: BPQD/Cys-8E/PTX + laser). Adapted with permission from ref. [68], Copyright, 2020, Haolin Chen et al.

Furthermore, Chen et al. synthesized a cysteine (Cys)-based poly-(disulfide amide) polymer and encapsulated the chemotherapy drug-paclitaxel (PTX) and black phosphorus QDs (BPQDs) into its inner space [68], and further modified with lipid-PEG to prepare biodegradable PTX/BPQD@Cys-8E nanoparticles (Figure 4g), which can be applied in photothermal optical coherence tomography (PT-OCT) guided PTT combined with PTX mediated chemotherapy for cancer treatment (Figure 4e and f). Simultaneously, the protective effect of Cys-8E polymer in outer layer significantly improved the stability and the photothermal performance of BPQDs and enhanced its effect in high-resolution PT-OCT (Figure 4h).

Generally, phototherapy mainly includes PTT and PDT, which can be applied to accurately kill tumor cells while causing minimal damage to normal tissues due to the controllable excitation light and irradiation position [51]. For example, Li et al. synthesized PEG modified two-photon black phosphorus QDs with photothermal and photodynamic effects that can be used in PTT/PDT-mediated cancer therapy [64]. PEG modification significantly improved the biocompatibility, water solubility, and stability of BPQDs, whereas the cytotoxicity was negligible. Consistently, Tao and coworkers prepared PEG coated two-dimensional antimonene QDs (PEG-AMQDs) by liquid stripping method [69]. The biocompatibility and stability of AMQDs were significantly improved due to the encapsulation of PEG, and the NIR-induced photothermal conversion efficiency of PEG-AMQDs also reached to 45.5%, exhibiting superior antitumor effect. Meanwhile, PEG-AMQDs can be rapidly degraded under NIR light with negligible cytotoxicity.

Recently, NIR II QD imaging plays a promising role in imaging-mediated surgical treatment of cancer due to its high temporal and spatial resolution [51]. For instance, Tian and coworkers prepared a two-channel NIR II imaging nanocomposite through combining donor–acceptor–donor dye (IR-FD) (1,100–1,300 nm window) and polymer-coated PbS/CdS core/shell QDs (>1,500 nm window), which can be used for synergetic imaging of tumors (IR-FD and QDs labeling) and tumor-invaded sentinel lymph node (SLN, QDs labeling) in primary/metastatic tumor treatment and SLN excision [67]. Simultaneously, polymer-coated QDs exhibit high FL intensity and stability (no noticeable bleaching after 5 h of continuous laser irradiation) and only picomolar dosages of nanocomposites is required to detect SLNs. Therefore, this study not only provides solid support for multi-channel FL imaging in visualizing different parts of complex diseases but also indicates that organic QDs NIR II imaging exhibit promising clinical applications for cancer resection. QDs NIR II imaging exhibits deeper tissue penetration and higher imaging resolution than visible and NIR I imaging, and have gathered wide attention in cancer imaging and treatment. At present, QDs are main semiconductor materials containing heavy metal elements, which seriously limit the clinical application of QDs from the perspective of biocompatibility and biotoxicity. Promisingly, both the construction of core-shell structures that can avoid leakage of heavy metal ions and QDs that do not contain heavy metal ions (such as carbon and Ag₂S QDs) may accelerate the clinical transformation of QDs.

2.1.4 Organic-platinum family metals nanocomposites

Platinum family metal nanomaterials, such as platinum, palladium, and ruthenium, exhibit excellent optical properties and catalytic activity, contributing to their application in cancer treatment, drug delivery, and catalysis [70,71,72]. Song and coworkers prepared porous hollow palladium nanoparticles modified with thermosensitive polymer for co-loading radioisotopes ¹³¹I and DOX, which can precisely control the drug release through repetitive laser irradiation and tumor microenvironment [70]. Moreover, ¹³¹I can be retained in the tumor exceeding 24 h without damaging normal tissue due to the unique interactions of palladium and iodine, which can effectively realize synergy of the photothermal, chemical, and radiation therapy in cancer treatment.

Simultaneously, Liang et al. synthesized F-127 modified vanadium tetrasulfide (VS₄) by solvothermal method, and further improved their sonosensitive properties by combining co-catalyst platinum nanoparticles with glutathione (GSH) for enhancing SDT in hypoxic tumors [72]. Platinum nanoparticles and GSH, as co-catalysts, can efficiently promote the production of reactive oxygen species (ROS) by capturing US-triggered electron-hole pairs to extend lifetime of the charge. Moreover, platinum nanoparticles can also catalyze hydrogen peroxide to produce oxygen, and then overcome tumor hypoxia and boost SDT to produce ¹O₂. Additionally, platinum-VS₄ can consume intratumoral GSH while being activated by US, resulting in the upregulation of ROS level for enhancing antitumor effect.

Furthermore, organically modified multiple platinum family metal nanomaterials have attracted the concern of researchers in cancer imaging and therapy [73,74]. For example, Ming et al. established a multifunctional nanoenzyme using HA encapsulated GOx-loaded Pd@Pt nanosheets for cancer starving enhanced CDT (Figure 5a) [74]. The encapsulation of HA enables the nanozyme to actively target CD44 overexpressed tumor cells while avoiding GOx-induced cytotoxicity to normal tissues, which are confirmed by inductively coupled plasma mass spectrometry and PA imaging (Figure 5b and e). After entering into the tumor cells, the HA localized at the outer layer of Pd@Pt GOx/HA was degraded by hyaluronidase (Hyase) to expose the GOx, which consumed oxygen to oxidize glucose for starvation therapy, and accompanied with H₂O₂ production and pH decrease in the tumor microenvironment, while Pd@Pt can decompose endogenous H₂O₂ to produce oxygen for promoting glucose oxidation and enhancing starvation therapy (Figure 5d). Moreover, Pd@Pt exhibited pH-responsive peroxidase activity and can catalyze H₂O₂ to generate a great deal of toxic ˙OH (Figure 5c), which is synergistic with GOx-mediated starvation therapy for cancer.

Figure 5

Organic-platinum family metal nanocomposites for cancer imaging and therapy. (a) Diagram of the fabrication procedure of the Pd@Pt GOx/HA nanoreactors and its theranostic application. (b) In vivo tumor PA imaging images before and after injection. (c) Toxic ˙OH detection images. (d) GOx and catalase-like activities of different groups. (e) Inductively coupled plasma mass spectrometry investigation of several cell types treated with Pd@Pt-GOx/HA. Adapted with permission from ref. [74], Copyright, 2020, American Chemical Society. (f) Schematic illustration of the preparation about Ru@CeO₂-RBT/Res-DPEG dual drug nanosystem. (g) Operative procedure and macroscopic orthotopic tumor by autopsy. (h) In vivo bioluminescence imaging of the orthotopic colorectal tumor of various groups at different days. (i) Synergistic therapy inhibits metastasis of colorectal cancer. After the treatments with saline and Ru@CeO₂-RBT/Res-DPEG + NIR (40 days), in vitro bioluminescence imaging was performed to assess the micro-metastasis in the primary organs and tissues. (intestine, heart, liver, spleen, lung, and kidney). Adapted with permission from ref. [79], Copyright, 2020, Elsevier Ltd.

Additionally, Au-platinum family metal nanocomposites have also been applied in cancer imaging and therapy [75,76,77,78]. Liu et al. prepared PEGylated Au@Pt nanodendrites by growing platinum nanobranches on gold nanoparticle for CT imaging and photothermal/radiation synergistic antitumor treatment [75]. PEGylation enhances the stability, dispersibility, and biocompatibility of Au@Pt nanodendrites. Both gold and platinum can enhance the radiation sensitivity and effectively kill tumor cells with PTT under low x-ray dosage and excitation power conditions. Simultaneously, superior CT signal of Au@Pt nanodendrites was confirmed in CT imaging studies, which can be used to precisely localize tumor cells and guide PTT/radio therapy for cancer imaging and therapy.

In addition to the organically modified Au-platinum family metal nanocomposites, nanocomposites made of platinum family metal and certain oxides have also been reported [79,80]. Zhu and coworkers synthesized bilayer PEG-coated Ru@CeO₂ yolk shell structure nanozyme (Ru@CeO₂ YSN), Co-loading Ru complex (RBT) and resveratrol (Res) to prepare a controlled release dual drugs delivery system (Ru@CeO₂-RBT/Res-DPEG) for colorectal cancer PTT and dual chemotherapy (Figure 5f) [79]. The results demonstrated that the double-layer PEG extended the blood circulation time and improved biocompatibility of the nanozyme, which could be effectively aggregated in the tumors. Moreover, Ru@CeO₂-RBT/Res-DPEG could catalyze H₂O₂ to produce oxygen, enhancing its own chemical and photothermal therapeutic effects. And the findings of bioluminescent imaging anti-metastasis assessment demonstrated that the nanozyme not only exhibited significant antitumor effects (Figure 5g and h) but also effectively inhibited the metastasis and recurrence of colorectal cancer (Figure 5i), which provides a new nanosystem for cancer imaging and therapy, as well as cancer metastasis inhibition. Although platinum-family metals and their organic nanocomposites play essential roles in cancer treatment, in consistent with other types of heavy metals, the cytotoxicity of platinum-family metals limit their applications as biomedicine, especially the high doses of them can cause mineral imbalances and serious illnesses in vivo, which should be further investigated [81]. Generally, the toxicity of this heavy metal is unavoidable, even after degradation, its toxicity still exists. However, the metal elements that are less toxic and necessary for organisms can be selected, such as Mg and Fe, and suitable modification strategies could be performed to improve their degradability, contributing to quick degradation into ions and further being discharged from the body after performing their functions. And even if there is residue in vivo, its toxicity to the organism can be tolerable, because the residual ions (Mg²⁺ and Fe³⁺) are also indispensable for organism.

2.1.5 Organic-Au nanocomposites

Au nanoparticles have received substantial attention in cancer imaging and therapy due to their remarkable optical characteristics, biocompatibility, and ease of modification [6], and Au nanoparticles coupled with organic materials have also been extensively studied in cancer treatment [82,83,84]. Recently, Zhang and coworkers prepared PEG and PDA encapsulated hybrid gold nanoparticles (Au@PDA-ss-PEGm) for tumors PA imaging and PTT activated by high concentrations of GSH (Figure 6a and c) [84]. The disulfide bonds on the surface of the hybrid nanoparticles can be ruptured under the higher concentration of GSH in tumor cells, and the outer PEG can fall off, resulting in a large number of clusters agglomerated due to the surface charge imbalance of Au@PDA, and further exhibiting the plasma-coupled enhanced photothermal effect and PA imaging (Figure 6c and d). The subsequent analysis indicated that Au@PDA-ss-PEGm exhibit outstanding biocompatibility and pharmacokinetic properties, and the photothermal conversion efficiency reached 46.5% when exposed to 808 nm excitation light, which can effectively kill tumor cells and suppress tumor recurrence (Figure 6b and e).

Figure 6

Organic-Au nanocomposites for cancer imaging and therapy. (a) Schematic illustration of synthesis procedure of Au@PDA-ss-PEGm and its theranostic application. (b) Images of tumor from the mice post-different treatments. (c) In vivo tumor PA imaging at different times after injection. (i: Au@PDA-ss-PEGm, ii: Au@PDA-PEGm, iii: PBS). (d) The PA intensity of tumor at different times. (e) Relative tumor volume change curve with time after PTT. (i: laser irradiation after excising 1/3 of tumor, ii: without laser irradiation after excising 2/3 of tumor, iii: laser irradiation after excising 2/3 of tumor). Adapted with permission from ref. [84], Copyright, 2022, American Chemical Society. (f) Diagram of the rGADA/KrasI preparation and its application for cancer treatments. (g) In vivo PA imaging of tumor locations obtained at specific time points after intravenous injection. (h) Histopathological analysis of tumors and livers at the end of treatment in different groups. (1: H&E, 2: immune-stained K-Ras, 3: Ki-67, 4: H&E, black arrows indicate the metastatic lesions, 5: yellow dotted lines circle the emphasized metastatic lesions from liver H&E staining, 6: black dotted lines circle the cytokeratin 7 (CK7) positive lesions, and the insert displays the CK7 staining in pancreatic cancer). L means laser. Adapted with permission from ref. [100], Copyright, 2020, Wiley-VCH.

Simultaneously, Yang et al. prepared a gold nanoparticle semiconductor polymer hybrid nanocapsule to enhance its optical property for tumor PTT and PA imaging [85]. The nanocapsule was prepared by self-assembling gold nanoparticles tethered by semiconductor poly(perylene diimide) (PPDI) and PEG, which can promote the aggregation of nanocapsule in tumor tissue by passive target. Moreover, the magnetic field can improve the optical absorption of PPDI due to a strong electromagnetic field existing between the two gold nanoparticles, resulting in the enhancement of the nanocapsule’s PA signal and photothermal effect, which can effectively pyrolyze tumor cells.

Additionally, organic (polymer, lipid, dendrimers, organic acids, etc.)-gold nanocomposites [86,87,88,89] are also employed for tumor targeting delivery of drugs and genes to achieve cancer imaging and synergistic therapy [90,91,92,93,94]. Wang et al. synthesized a 40 nm macroporous gold nanoframeworks (HA-4-ATP-AuNFs) encapsulated with 4-ATP-coupled HA [94], which can be employed for Raman imaging and SERS fingerprinting due to the coupling of Raman reporter 4-ATP (4-aminothiophenol). The nanostructure exhibited high absorption in the NIR-II, providing an optical foundation for deep tumor PA imaging and PTT. Simultaneously, photothermal-chemo synergistic tumor therapy can be achieved by excitation of light irradiation at NIR-II through actively targeting CD44 overexpressed tumor cells of HA-encapsulated DOX-loaded macroporous gold nanoparticles. The subsequent results further indicated that dual-mode imaging guided NIR-II photochemical therapy with the nanostructure can almost fully eliminate the tumor.

For gene delivery, Dai et al. prepared a Janus CS/PEGylated GNR complex (J-Au-CS) with variable crosslinking and GNR length breadth ratio, on the basis of J-Au-CS, and cationic polymer CD-PGEA (cyclodextrin-two-armed ethanolamine-functionalized PGMA (poly(glycidyl methacrylate)) was connected to the surface of CS to construct J-ACP [95]. Thereafter, the antioncogene P53 was loaded on J-ACP surface for achieving PA imaging-guided PTT, resulting in significant enhancement of gene delivery for synergistic cancer treatment. Furthermore, they reasonably postulated that PEG encapsulation would improve the biocompatibility and prolong the circulation time of GNRs in vivo, promoting J-ACP/P53 accumulation in tumors. Therefore, both in vivo and ex vivo analysis indicated that J-ACP/P53 exhibited severe toxicity on cancer cells under NIR light, which provides a novel nanosystem for imaging guided effective cancer synergistic treatment.

Simultaneously, the combination of other nanomaterials with gold-organic nanomaterials for cancer imaging and therapy are also being studied [96,97,98,99,100]. For example, Jia et al. prepared rGADA (Figure 6f), a lipid bilayer encapsulated RGO@gold nanostar that can be loaded with mutant anticancer gene plasmid, KrasI, and realize PTT of pancreatic cancer guided by photothermal PA imaging (Figure 6g) under NIR [100]. FA conjugated with liposomes on rGADA surface can specifically bind to the folate receptor expressed on the surface of tumor cells, significantly enhancing the tumor targeting and the endocytosis of the nanomaterials. Furthermore, both in vivo and in vitro analysis indicated that the rGADA/KrasI not only exhibited superior therapeutic effects on pancreatic cancer but could also effectively inhibit pancreatic cancer metastasis (Figure 6h) with negligible toxicity to organism.

Recently, the nanocomposites of gold doped with MOF containing other materials have also been applied in cancer imaging and therapy [101,102,103,104,105,106]. Liang and coworkers prepared a nanocluster structure for early cancer diagnosis and treatment [106], in which Zr-MOF@Au was constructed by immobilizing gold nanoclusters on the Zr-MOF, and the surface of Zr-MOF@Au was modified with Quasar and Cy5.5 labeled DNA strands. The probe’s surface-mounted DNA strand and two types of fluorescent dyes conferred the nanocomposite sensitively detecting the microRNAs closely related with cell cancerization in vivo. Moreover, the nanoprobe exhibited high photothermal conversion efficiency and could accurately identify tumors at a safe power dose, which is extremely important for early cancer diagnosis and removal. Until now, although researchers have reported a variety of gold based therapeutic nanoplatforms, most of them are only evaluated in animal models, and few have exhibited potential for clinical application. Besides the high cost of nanoplatforms production, the main problems hindering the clinical application of gold-based nanotherapeutic platforms are still biocompatibility and cytotoxicity, which can be affected by various factors such as size, surface modification, and cell type. Therefore, the collaboration of scientists from various fields is crucial for the preparation of gold-based nanoplatforms with appropriate properties for clinical application.

2.1.6 Organic-metal oxide nanocomposites

A great number of metal oxides (such as TiO₂, CeO₂, MnO₂, Fe₃O₄, and Fe₂O₃) combined with organic materials have been employed in cancer imaging and therapy. While magnetic nanoparticles with unique physical feature (magnetic and optical properties), such as Fe₃O₄ and Fe₂O₃ can be applied in MR imaging, magnetic hyperthermia, PTT, and PDT for cancer [107,108,109,110,111,112]. For instance, Li and coworkers demonstrated that mannose modified porous hollow iron oxide nanoparticles loaded with 3-methyladenine (a small molecule inhibitor of P13K γ) and can target tumor-associated macrophages with high expression of mannose receptors [112]. The combination of the iron oxide nanoparticle and 3-methyladenine inhibited the expression of P13K γ, promoted the expression of transcriptional factor NF-κB p65, and further induced tumor-associated macrophages to transform into pro-inflammatory M1 type macrophages, which can effectively activate the immune response to suppress tumor growth.

Moreover, Liang et al. prepared Fe₃O₄@PEL (porphyrin-grafted lipid) core-shell nanoparticle for FL and MR dual-mode imaging-guided ferroptosis enhanced PDT (Figure 7a) [109]. The Fe₃O₄@PEL exhibited negligible cytotoxicity and no significant histological damage or inflammation (Figure 7d), which is likely contributed by the enhanced biocompatibility of the nanoparticles with PEL encapsulated on the Fe₃O₄ surface. Moreover, the self-assembly of PEL nanoparticles on the Fe₃O₄ surface contributed to increase the loading capacity of porphyrins, and the mass ratio of the PEL in Fe₃O₄@PEL could reach to 50%. Furthermore, in vivo analysis have indicated that, in the presence of laser irradiation, MR and FL imaging guided ferroptosis enhanced PDT and exhibited superior inhibition on tumor growth (Figure 7e), while Fe₃O₄@PEL can also accelerate the Fenton reaction in the presence of RAW 264.7 macrophages to produce ˙OH for tumor treatment (Figure 7b and c).

Figure 7

Organic-metal oxide nanocomposites for cancer imaging and therapy. (a) Schematic of Fe₃O₄@PGL nanoparticles for therapeutic application. (b) Comparison of ROS production in two groups with and without the existence of ROS scavengers, HT-29 cell group serve as a control. (c) Fluorescent images without and with the existence of ROS scavengers and quantification of ROS production. (d) Histological study of major organs at different times after injection of Fe₃O₄@PGL. (e) Change curves of tumor volume with different treatment. Adapted with permission from ref. [109], Copyright, 2021, American Chemical Society. (f) The degradation procedure of y-UCM/M&D-PEG nanocomposites in cancer cells. (g) Drugs loading and preparation of y-UCM-PEG YSNs. (h) NIR-II FL bioimaging images of tumor (up) and abdomen (down) post-administration with y-UCM/M&D-PEG nanoparticles. (i) Relative tumor volume change of different groups after treatment. (j) Comparison of in vivo tumor PA imaging before and after y-UCM/M&D-PEG nanocomposites administration. Adapted with permission from ref. [119], Copyright, 2020, American Chemical Society.

Recently, nano-TiO₂ has gradually became the representative of the ideal sonosensitizers, and its organic nanocomposites have been extensively studied in multi-mode cancer therapy, such as SDT [113,114,115,116]. Zhang group prepared a photothermal material, polypyrrole (PPy) encapsulated mesoporous TiO₂ nanocomposites (mTiO₂@PPys) [113], which can not only generate ROS under US for SDT of tumor but also be employed as a carrier to load honokiol for chemotherapy, and the rates of drug loading reached to 6.5 ± 0.3%. mTiO₂@PPys can also be used as photothermal agent due to the existence of PPy, and exhibited a photothermal conversion efficiency of approximately 35.3%. Furthermore, in vivo US and PA imaging analysis indicated that a certain concentration of mTiO₂@PPys can produce robust US and PA signals. Consequently, mTiO₂@PPys will be promisingly employed for US/PA imaging-guided chemical, photothermal, sonodynamic three-mode synergistic cancer treatment.

Interestingly, a pH-responsive polymer-porous CeO₂ nanorod (PN-CeO₂-PSS) was prepared for catalyzing intratumor oxygen to produce highly toxic superoxide anion ( O 2 ˙ − ) for tumor CDT [117]. In acidic tumor microenvironment, the hybrid material exhibited high oxidative activity, trapped oxygen and biological substrates inside, and catalyzed the conversion of oxygen to O 2 ˙ − by charge transfer, while this oxidative activity can be inhibited in a neutral environment, avoiding damage to normal cells. However, in the absence of an outer layer of polymer-sodium polystyrene sulfonate, the oxidative activity of PN-CeO₂ is very low under any pH conditions, which may be attributed to polymer loss resulting in its inability to capture oxygen and biological substrates for catalytic reactions. Despite its poor oxidative activity, PN-CeO₂ exhibited considerable antitumor effect, which could be attributed to its catalase activity by converting H₂O₂ into toxic ˙OH in tumor microenvironment.

Furthermore, organic MnO₂ nanocomposites have also been studied for image-guided tumor therapy by virtue of its tumor microenvironmental response and MR imaging capabilities [118,119,120,121,122]. For instance, Zhuang et al. prepared a YSN consisting of an up/down conversion nanoparticle (UCNP) core and a mesoporous manganese dioxide (MnO₂) shell for multimodal imaging-guided cancer PDT and chemotherapy [119], and then the PEG modified YSN can be loaded with photosensitizer MB (loading efficiency is 30%) and antitumor agent DOX (loading efficiency is 60%) (Figure 7g). Theoretically, the PEG modification improves the solubility and stability of the YSN, and the outer MnO₂ shell will be degraded to release the drugs after entering into the tumor cells, then Mn²⁺ is generated for tumor-specific MR imaging, and oxygen is generated to relieve tumor hypoxia for enhancing the efficiency of PDT (Figure 7f). Furthermore, PA imaging of MB and NIR-II FL imaging of UCNP (Figure 7h and j) can accurately guide cancer photodynamic/chemical therapy through detecting the distribution of materials within tumors (Figure 7i).

Additionally, nanocomposites containing metal oxides and other nanomaterials have also received considerable attention in cancer imaging and therapy [79,80,123,124]. PEG-coated Ru@CeO₂ yolk shell structure was prepared for chemical and photothermal treatment of colorectal cancer [79]. Simultaneously, Xu et al. also prepared PEG modified porous platinum@CeO₂@MnO₂ core-shell nanocomposites (Pt@CeO₂@MnO₂), and the composite can be loaded with DOX for PA imaging mediated chemical/photodynamic/photothermal tri-mode cancer treatment [80]. Although there are only few metal oxides or their organic nanocomposites reported that can be used in clinical cancer treatment, it is believed that they will be promisingly applied in cancer imaging and therapy when we can accurately control all the properties of metal oxides, particularly their biocompatibility and biosafety.

2.1.7 Other organic-metal based nanocomposites

Besides the organic-metal nanocomposites discussed previously, there are still other types of organic-metal based nanocomposites for cancer imaging and therapy, such as organic-metal sulfides [125,126,127,128], metal selenides [129,130], and organically modified UCNPs doped with Lanthanides. HA coupling with two-dimensional molybdenum sulfide (HA-MoS₂) synthesized by Shin and coworkers can promote the accumulation of HA-MoS₂ in tumors and improve the endocytosis of MoS₂ by tumor cells via specific binding to HA receptors [128]. Further, FL and PA imaging can accurately detect the distribution of HA-MoS₂ in vivo and guide PTT under NIR irradiation. Simultaneously, Liu group prepared hollow Bi₂Se₃ nanoparticles via cation exchange and Kirkendall effect in one pot, and then the nanoparticles were encapsulated with PEG and perfluorocarbon (PFC) (dissolved oxygen as oxygen carrier) was loaded into the hollow interior of the nanoparticles [130]. The PEG-Bi₂Se₃@PFC@O₂ can enhance tumor oxygenation through oxygen release under NIR irradiation and overcome tumor hypoxia radioresistance, and thereby enhance the tumor radiotherapy effect.

Because of the luminescent property under continuous-wave NIR light, lanthanide-doped UCNPs are considered to be excellent light imaging contrast agents [131], and can be further coupled with other functional components to establish multifunctional nanoplatforms for imaging-guided cancer therapy [73,132,133]. Kuang et al. prepared polyethyleneimine-coated co-doped Yb³⁺, Tm³⁺, Gd³⁺ upconversion nanoparticles (PUCNPs) to co-load photoactivated polymerized Pt prodrug and SiRNA (targeting Polo-like kinase 1; Plk1) [73]. PUCNPs@Pt@siPlk1 can convert NIR light into ultraviolet and visible light for upconversion luminescence imaging, and the transformed light can further activate polymerized Pt prodrugs for releasing toxic Pt(ii) and siPlk1 for tumor synergistic treatment in chemotherapy and RNA interference gene therapy, while the doping of Yb³⁺, Tm³⁺, and Gd³⁺ also confers UCNPs with the ability of CT and MR imaging. Consequently, the lanthanide-doped UCNPs exhibit great potential for multimodal imaging mediated light-controlled drug/gene delivery in cancer imaging and therapy.

2.2.1 MOFs

MOF, also known as porous coordination polymers, are characterized by flexible or rigid porous structures, which are constructed by the coordination bonding of metal ions and organic ligands [134]. Since the discovery of MOFs in the 1990s, they have attracted substantial attention due to their diverse combination types, large surface area and adjustable biocompatibility [17]. Moreover, nMOFs are smaller in size than MOFs and display a wider application potential, particularly in the field of biomedicine. Simultaneously, nMOFs possess both the physical and chemical properties of organic ligands (biocompatibility and biodegradability) and metal ions (optical, magnetic, and catalytic properties), collectively contributing to their potential application in cancer imaging and therapy [135,136,137,138,139]. For example, Yang and coworkers prepared iron-containing metal-organic frameworks (MOF (Fe)) by combining Fe³⁺ with organic ligands [138], MOF (Fe) can not only be used as a catalase analog to convert H₂O₂ into highly toxic ˙OH but also under the synergistic action with the autophagy inhibitor, chloroquine (inhibit autophagosome by deacidifying lysosomes to cut off the protective pathway of severe oxidative stress in tumors), the combined treatment can perform the superior antitumor effect. Simultaneously, a defect rich Ti-based metal-organic framework (D-MOF (Ti)) was applied as sonosensitizers to produce high levels of ROS under US (Figure 8a), and exhibited Fenton-like effect when combined with SDT due to the existence of Ti³⁺ (Figure 8b and c) [135]. It is also worth mentioning that after performing its function, D-MOF (Ti) could be degraded into small fragments in vivo and excreted in urine, which effectively avoids the potential off-target toxicity (Figure 8d).

Figure 8

MOFs for tumor therapy. (a) Diagram of preparation and cancer treatment of D-MOF(Ti). (b) Images of ROS production in different groups. (c) Cell viabilities of 4T1 cells in groups received different treatments. (d) Quantification of Ti in excrement at different times post-injection of D-MOF (Ti) (dose: 15 mg/kg). Adapted with permission from ref. [135], Copyright, 2021, Wiley-VCH. (e) Schematic of acid-triggered H₂/DOX release from DOX@Fe-MOF nanocrystals for overcoming cancer resistance/metastasis. (f) H₂ releasing behaviors under different pH values. (g) Intra-tumoral expression of MMP-2 (metastasis-related matrix metalloproteinase-2) examined by western blotting where glyceraldehyde-3-phosphate dehydrogenase (GAPDH) serve as internal parameters. (h) Tumor photographs and tumor weight statistics after treatment in different groups. (i) Body weight change curves of tumor-bearing mice during treatment. Adapted with permission from ref. [148], Copyright, 2022, Yao et al.

In addition to metal ions, organic ligands in nanocomposites can also play a therapeutic role in the cancer therapy. For instance, Wang et al. combined organic porphyrins with metal ions to construct nano-porphyrin MOF, and then prepared ultra-small porphyrin MOF QDs by liquid phase stripping [140]. For tumor PDT, porphyrin can be taken as an excellent photosensitizer converting oxygen into toxic singlet oxygen, and the ROS production induced by ultra-small MOF QDs is twice that of the normal porphyrin MOF or PEG-porphyrin MOF under the same illumination condition.

Moreover, besides the direct antitumor effect, nMOFs with porous structure and large specific surface area are ideal cargos for drug delivery (Such as drugs, proteins, nucleic acids, and dyes) [141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156]. Compared with traditional inorganic and organic nanocarriers, nMOFs exhibit superior capacity of drug loading (due to its high specific surface area and large pore size) and controllable drug release, biodegradability (due to metal ion and organic ligand linked by weak coordination bond), and the capacity of accommodating cargo molecules with different physicochemical properties (due to the diversity of MOF structure and adjustable size) [11]. For instance, Kim et al. synthesized a HA-coated nano-Zr-based porphyrin MOF, named HA-PCN-224, which was used as a nano-carrier for loading DOX [145]. HA-PCN-DOX could target tumor cells with CD44 overexpression, after being absorbed by tumor cells, HA is digested by HA enzyme and the loading DOX is released for performing chemotherapy, which synergistically acts with PDT to improve antitumor effect.

Simultaneously, Yao and coworkers recently synthesized a novel acid-degraded Fe-porphyrin metal-organic framework (Fe-MOF) by coordinating Fe atom and porphyrin, Fe-MOF can load drugs and provide H₂ (Figure 8f) for H₂-assisted chemotherapy contributing to overcome MDR and inhibit tumor metastasis (Figure 8e) [148]. Interestingly, H₂ could not only inhibit the expression of tumor-related proteins and tumor metastasis, and enhance the sensitization of tumor cells to DOX chemotherapy (Figure 8g and h) but also ameliorate the toxicity of DOX on normal cells (Figure 8i). Importantly, Fe and porphyrin have been licensed for clinical application, which provide safety guarantee of MOF applied in clinic. Furthermore, Zhang et al. designed a dual-sonosensitizer nanosystem loaded with alkyl radical generator (AIPH) for tumor SDT [157]. Under US treatment, AIPH can produce toxic alkyl radicals and nitrogen, which could strengthen both the effects of SDT and the penetration effect of Zr-MOF@AIPHS in tumor therapy. Additionally, based on the porphyrin structure and the resulting nitrogen gas, Zr-MOF@AIPH can also be applied for PA, FL, and US imaging to guide its own delivery and determine the ideal treatment duration for enhancing tumor SDT.

Furthermore, the combination of MOF with other types of nanomaterials have also been applied in cancer imaging and therapy [101,106,158,159,160,161,162,163,164]. Huang et al. synthesized a bovine serum albumin (BSA)-MnO₂ coated MOF, which was loaded with siRNA to inhibit the expression of pyruvate kinase muscle isozyme M2(PKM2), a key enzyme in glycolysis [164]. And BSA-MnO₂ can act as catalase in tumor acidic environment for catalyzing H₂O₂ to produce oxygen, which could relieve the hypoxia in tumor microenvironment, inhibit the overexpression of hypoxia-inducible factor-1, and enhance the antitumor effect. Simultaneously, Mn²⁺ can be used for real-time MR imaging to monitor drug release and evaluate the final therapeutic effect. Accordingly, Ding and coworkers prepared a nanocomposite by growing gold nanoparticles on a Fe-containing metal-organic framework (Fe-MOF), and PEG encapsulated Au/Fe-MOF was loaded with camptothecin (CPT) for tumor CDT and chemotherapy [161]. Under the condition of high concentration phosphate in tumor microenvironment, this nanocomposite can be dissolved and CPT was released for chemotherapy, as well as gold nanoparticles can oxidize glucose to generate H₂O₂ in tumor tissues and supply substrate for iron(iii) meso-tetra (4-carboxyphenyl) porphine chloride (TCPP (Fe))-mediated Fenton reaction. The abovementioned results indicate that combining chemotherapy with CDT exhibit an obvious inhibition on tumor growth.

Recently, substantial achievements in preliminary studies have been made in nMOFs by virtue of their advantages in variability, large specific surface area, diverse functionalities, and high stability. And the selection of metal ions (Ca, Mg, and Fe) with high biocompatibility to coordinate with endogenous or bioactive molecules will be the future research direction of nMOFs applied in clinic. However, there are still quite a few obstacles in the application of nMOFs in cancer imaging and therapy, especially the most serious of which being their toxicity. The toxicity of nMOFs not only results from themselves but also is dependent on the tolerance of living bodies. Unfortunately, the recent toxicity assessments of nMOFs are mainly limited to acute toxicity detection, and the crucial chronic toxicity evaluation is rare, resulting in the uncertainty of long-term safety of nMOFs in clinic. Consequently, long-term monitoring of the metabolism and accumulation of nMOFs in vivo play important roles in promoting the development of nMOFs, and more attention should be paid on these core tissues.

2.2.2 Organosilica nanoparticles

MSNPs have attracted extensive attention in drugs delivery due to its favorable specific surface area, biocompatibility, and stability. However, the inert Si-O-Si framework of silica results in poor biodegradability, thereby partly restricting their clinical applications [165]. To address the deficiency of poor biodegradability, new biodegradable organic–inorganic hybrid nanomaterials-hollow mesoporous organosilica nanoparticles (HMONs) were produced by directly doping organic functional groups into the framework of silica nanoparticles [165,166,167,168,169,170], such as GSH-responsive degradable HMONs produced by directly doping disulfide bonds into the silica frameworks. As a nanocarrier, HMONs will perform better than MSNPs because of its excellent biodegradability. It has been reported that PEGylated hollow mesoporous organosilica nanocapsules (HMONs@PEG) could realize the target biodegradation and DOX release in tumor cells to strengthen the chemotherapeutic effect, because physiologically active disulfide groups (–s–s–) are directly incorporated into the silica framework (Figure 9a). This disulfide bonds can be broken by GSH in the tumor cells (Figure 9b), and then the nanocapsule slowly degrades for controlled release of DOX maintaining the long-term effect of chemotherapy (Figure 9c and d) [170].

Figure 9

Organosilica nanoparticles for cancer imaging and therapy. (a) Diagram of fabrication of HMONs and its GSH reducing response degradation mechanism. (b) Transmission electron microscopy (TEM) images of HMONs@PEG after 48 h in different conditions. (c) DOX-releasing percentage change in different conditions. (d) Tumor volume change curves during different treatments. Adapted with permission from ref. [170]. Copyright, 2017, Elsevier Ltd. (e) Scheme for the synthesis of small-sized HMONs, schematic illustration for Pt@HMONs without ZC-MOF gating and Pt@HMONs with ZC-MOF gating in neutral and acidic environment. (f) In vivo FL images of tumor-bearing mice at different times and ex vivo FL images of major organs and tumors after injection for 48 h. (g and h) Pt release profiles of Pt@HMONs and Pt@HMONs@ZC under different pH values. (i) Copper ion release profiles of Pt@HMONs@ZC under different pH values. (j) Relative tumor volume change curves during different treatments. Adapted with permission from ref. [158], Copyright, 2022, Wiley-VCH.

Simultaneously, Tang et al. also produced thioether/phenylene dual-hybridized HMONs by ammonia-assisted hot water etching, which will be slowly degraded in the presence of GSH and exhibit very low hemolysis due to the incorporation of thioether and phenylene [165]. Generally, modification of HMONs with Mo(vi)-based polyoxometalate after loading Mn₂(CO)₁₀ confers them to self-assemble under the tumorous mild acidic environment and boost the aggregation of HMONs at the tumor. Further, intra-tumoral GSH-responsive Mo(vi)-Mo(v) transition and HMONs degradation not only enable intra-tumoral PA imaging and PTT, but also activate Mn₂(CO)₁₀ to effectively release CO for PTT-enhanced CO gas therapy for cancer therapy.

Additionally, although the naked HMONs have a large drug-loading space, it also faces the problem of drug leakage in advance. Therefore, encapsulating mesoporous organosilica with suitable materials plays critical role in improving drug loading and target release of drug in tumor. Based on the superior biodegradability of the MOF in tumor microenvironment, the HMONs encapsulated by MOF exhibit both high drug loading capacity and target release of drug in tumor; meanwhile, the metal ions generated after MOF biodegradation can also be used for cancer imaging and therapy [158,162]. For instance, Ma et al. loaded cisplatin into Zn/Cu co-doped MOF (ZC-MOF) encapsulated HMONs for tumor chemo-CDT (Figure 9e) [158]. In the tumor’s slightly acidic environment, MOF can be dissolved and cisplatin was released for tumor chemotherapy (Figure 9g and h), simultaneously, the release of Cu²⁺ catalyzes intra-tumoral H₂O₂ to produce toxic ˙OH for CDT of tumors (Figure 9i), which can also consume intra-tumoral GSH to enhance the therapeutic effect of CDT and cisplatin (Figure 9f and j). Another study found that the MOF (Fe) can be successfully combined with PDA-modified HMONs to construct organic–inorganic hybrid nanoparticles (HMONs-PMOF), and DOX and indocyanine green were, respectively, incorporated into the inner and outer space of MOF porous structures [162]. This nanoparticle can achieve pH/NIR dual response release of DOX for MR and PA imaging-guided PTT/chemotherapy, and exhibit outstanding synergistic antitumor effects. Conclusively, the organic–inorganic hybrid nanostructures produced by combining HMONs and MOFs are novel and promising multifunctional nanocomposites for cancer therapy.

MONs not only inherit the advantages of high specific surface area, excellent stability, and easy modification of MSNPs but also overcome the disadvantages of MSNPs’ difficulty to degrade in vivo. MONs can respond to specific biological stimuli and degrade, such as MONs introducing disulfide bond will gradually degrade under the action of GSH. Simultaneously, MONs have a low hemolysis rate and high biocompatibility, which contribute to the great potential of MONs in clinical applications. However, the controlled synthesis and biological evaluation of MONs is still in the initial stage, and after systematic biosafety evaluation, we believe that MONs is highly likely to achieve clinical transformation and application in cancer therapy in the near future.

2.2.3 ACPPs

Being similar to nMOFs, ACPPs are also a type of nanoscale metal coordination polymers, which are constructed from metal ions and organic ligands, and will be degraded into metal ions and small organic ligands in vivo for being excreted from the body. However, the structural crystallinity of ACPPs is quite different from nMOFs with highly ordered crystalline structure, while ACPPs have very low crystallinity and no framework structures [16]. Precisely because of this amorphous feature that the organic ligands in ACPPs are no longer limited to the framework building blocks, and any organic ligands with suitable chelating points are available, indicating that there are wider range of organic ligands and metal ions that can be used to prepare ACPPs. For example, photosensitizers [171–174] and chemical drugs [175–178] used as organic ligands are combined with metal ions (such as Fe³⁺, Zn²⁺, Mn²⁺, Gd³⁺, etc.) to produce multifunctional ACPPs, and the generated ACPPs are likely to exhibit higher drug loading capacity than traditional drug carriers when chemical drugs are served as organic ligands. Furthermore, the preparation method of ACPPs is relatively simple and independent of rigorous reaction conditions, which can be generally produced by mixing organic ligands and metal ions under mild conditions. Chen et al. prepared FA-modified ACPPs using Gd³⁺ and cypate with carboxyl group, which can be loaded with curcumin for imaging guided chemotherapy and PTT of tumors [171]. In the generated ACPPs, cypate, a photosensitizer with NIR absorption/emission properties, was utilized as PA imaging contrast agent and photothermal agent, while Gd³⁺ was used as T1-weighted MR imaging contrast agent for tumor MR imaging. Simultaneously, FA can effectively accumulate the ACPPs in tumor cells with FA receptor overexpression, and enhance the uptake efficiency through FA-mediated endocytosis. After entering into the tumor cells by endocytosis, curcumins are rapidly released under the dual stimulation of acidic microenvironment and photothermal treatment, which significantly enhance the anti-tumor effect of chemotherapy and PTT.

As mentioned above, besides the photosensitizers, chemical drugs can also be used as organic ligands to prepare ACPPs for cancer therapy. For example, Zhang and coworkers produced ACPPs by the integration of gallic acid and Fe³⁺ for MRI-guided chemo-photothermal synergistic therapy [178]. Simultaneously, the surface of this ACPPs was functionalized with PEG modified poly(lactic-co-glycolic acid) to enhance its physiological stability and biocompatibility, which could avoid recognition and phagocytosis by the reticuloendothelial system, prolong the circulation time of the ACPPs in vivo, and contribute to the enrichment of ACPPs at tumor tissues through the enhanced permeability and retention effect. Further, with the accumulation of ACPPs at the tumor tissues, the MR imaging signal at the tumor is gradually enhanced, which can be used for MR imaging to provide real-time and accurate guidance for PTT and chemotherapy. Once entering into cancer cells by endocytosis, the ACPPs will be gradually biodegraded and gallic acid will be released in lysosomes, and the combination of gallic acid-induced chemical effect with PTT can effectively kill cancer cells. Moreover, Li et al. synthesized a series of DNA-based ACPPs by self-assembling DNA and Fe³⁺, and the size of prepared ACPPs can be regulated by controlling the ratio and concentration of Fe³⁺ and DNA, it is worth mentioning that the loading rate of DNA in the prepared ACPPs was 50–73.8% [179]. Additionally, taking Cu²⁺ or Fe³⁺ as metal ion sources and 3,3′-dithiobis (propionohydrazide) as organic ligand, Xu et al. prepared a hollow ACPPs that can load DOX for synergistic cuproptosis/ferroptosis/apoptosis during anti-tumor therapy [180]. Actually, in the past decades, these ACPPs have exhibited various advantages, such as easy degradation and excretion, high drug loading efficiency, simple preparation process, and diverse structure, which attract more attention and make great progress in cancer imaging and therapy.