English

• 1. Introduction

  The kidney is an essential organ responsible for waste metabolite elimination, electrolyte homeostasis, and blood pressure regulation through the renin-angiotensin-aldosterone system [1]. The cancerization of this organ is a serious threat to human health and life. Unfortunately, renal cell carcinoma (RCC) is one of the most commonly diagnosed cancers. About 434,000 new cases and 155,000 new deaths related to kidney cancers worldwide are reported in 2022, among which RCC accounts for 80%-90% with a male-to-female patient ratio of around 2:1 [2]. The asymptomatic RCC is usually diagnosed incidentally during imaging examinations for irrelevant issues. Also, owing to the high heterogeneity in RCC imaging, traditional methodology (i.e., ultrasonography, computed tomography, and magnetic resonance imaging) has limited capability and sensitivity to reflect adequate information on the early stage RCC [3]. Only a few patients are identified at the early clinical assessment before RCC progression to kidney damage. For RCC management, nephrectomy is the preferred treatment for localized tumors, and the recurrence rate is generally below 25%. However, this number rises to 40% after surgery for the cases of advanced RCC [4,5]. Adjuvant therapy (radiotherapy, chemotherapy, immunotherapy, etc.) is often performed to consolidate the effect of nephrectomy. While some patients may benefit from the treatments, the toxicity and resistance of the involved drugs put forward new challenges for prognosis [6,7]. Therefore, developing combination therapies based on the RCC characteristics (more specifically, tumor microenvironment) and the traditional therapy limitations (e.g., low specificity, undesired side effects, physiological toxicity, and drug resistance) is of great significance for improving the survival rate and life quality of the patients.

  In recent years, the blooming of nanotechnology has provided opportunities for RCC therapy updates. Nanomaterials usually refer to the 1–100 nm small structures (in one dimension at least). The range of which matches the operation scale in living cells for most biological molecules. As a result, nanomaterials display enormous potential in RCC diagnosis and treatment. For kidney diseases concretely, pathological changes of the glomerular basement membrane (GBM) permit the entrance of nanomaterials with a size below 10 nm [8]. The 10–200 nm nanomaterials may enter through the enlarged GBM fenestration of the diseased kidney [9,10]. While for larger nanomaterials (hundreds-nanometer level), endothelium transcytosis at tubule-adjacent capillaries may work [11]. In addition, the designability of nanomaterials from the exterior to the interior demonstrates the feasibility of optimal therapeutic effect, acceptable toxicity, and smart outcomes, which would revolutionize traditional treatment options. The surface of nanomaterials could be modified on demand according to the tumor microenvironment for better biocompatibility and tumor targeting. For example, nanomaterials decorated with recognizable ligands would access the target cells easily through receptor-ligand interactions [12]. Deep inside the nanomaterials, tunable pore structures facilitate the loading of desired functionalities, including but not limited to drugs, proteins, contrast media, and immune molecules [13]. The protection of nanomaterial carriers not only prolongs the circulation of therapeutic agents and minimizes the toxicity on adjacent healthy tissue [14], but also modulates drug release as well as switches on/off the functional unit at the precise target sites [15]. Consequently, nanomaterials are anticipated to achieve a seamless integration of diagnostic and therapeutic interventions. Taking a closer look at the nature of nanomaterials, the combination of elements, the ordered arrangement of atoms, and the size differences in dimensions endow nanomaterials with various physicochemical properties. In response to the external field and/or tumor microenvironment, nanomaterials may realize energy conversion, trigger catalytic reactions, and activate specific biological signaling pathways. Although nanomaterials are still far from satisfactory in comparison to the intelligence and efficiency of natural enzymes, these functions display great potential in disease intervention. Overall, tailoring the functionality of nanomaterials in conjunction with the unique properties of RCC and cutting-edge therapeutic techniques emerges as one of the most promising strategies to achieve remarkably enhanced therapeutic outcomes.

  Herein, a comprehensive summary of recent progress in RCC treatment using inorganic nanomaterials is provided (Fig. 1). Beyond the reported articles about a similar topic [16–19], this review deconstructs the role of inorganic nanomaterials (and their functional units) in RCC therapy from the perspective of material science. Moreover, according to the current limitations and concerns, further essentials for developing smart and effective solutions against RCC are put forward. The corresponding discussion and outlook would hopefully guide the future design of a nanomaterial-based therapeutic platform for RCC treatment, which remains to be reported.

  Figure 1

  

  Figure 1.  Overview of inorganic nanomaterials for RCC treatment.

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  2. Inorganic nanomaterials in RCC treatment

  2.1 Carbon nanomaterials

  Prized for their tunable surface structure, multifunctional loading properties, long-term efficacy, and good biocompatibility, carbon nanomaterials (generally including carbon quantum dots, carbon nanotube, (reduced) graphene oxide, graphdiyne, etc.) exhibit great potential for biomedical applications [20–22].

  Constructed by cylindrical and nested graphene structures, multi-walled carbon nanotubes (MWCNTs) could release extensive vibrational energy after near-infrared (NIR) irradiation [23]. This property endows the photothermal ablation of lesions without direct access to the specific site. Using MWCNTs as effective energy transducers, Torti et al. investigated the viability of photoablation for RCC treatment [24]. It was found that with the length of nitrogen-doped MWCNTs satisfying the classic antenna theory, a significant temperature increase and subsequent cancer cell death were realized. The results demonstrated the versatility of nitrogen-doped MWCNTs as promising energy-delivery and cytotoxic agents. Further investigation on MWCNTs by Torti and coworkers systematically documented the thermal effect and the immunohistochemical behavior [25]. After intratumor injection of Pluronic F127-stabilized MWCNTs suspension, magnetic resonance temperature mapping was performed to monitor the thermal effect after NIR irradiation. The average temperature of 74 ℃ recorded on the MWCNTs-loaded RCC tumor after NIR laser irradiation was higher than on the control tumors (46 ℃). The measurement of heat shock proteins as thermal stress markers further confirmed temperature elevation for the laser-coupled MWCNTs group at the deeper tumor sites. Moreover, an obvious survival advantage was also observed in the RCC tumor-bared mice treated with the combination of MWCNTs and NIR irradiation.

  Graphene oxide (GO) is another competent carbon nanomaterial for RCC treatment. The hydrophilicity, sufficient surface area for drug loading, and abundant oxygenated groups of GO support its functionalization. Based on these advantages, Xu's group fabricated a GO-based theranostic nanocomplex for RCC therapy [26]. The sp²-hybridized nature and rich carboxyl groups of GO facilitated the chemical coupling of bovine serum albumin-stabilized Gd₂O₃ nanoparticles (BSA-Gd₂O₃), which is an efficient contrast agent in magnetic resonance imaging (MRI). Meanwhile, the G-quartet DNA aptamer AS1411 was also conjugated on GO as the targeting unit to recognize RCC tumor cells, and the anticancer drug doxorubicin (DOX) was also loaded. The obtained GO/BSA-Gd₂O₃/AS1411-DOX nanomaterial could not only identify 786-O human RCC cells by displaying stronger MRI contrast enhancement but also release the therapeutic DOX drug stimulated by the acidic RCC tumor microenvironment, which provided opportunities for on-line diagnosis and control of the RCC progression. The work reported by Liu et al. also took advantage of GO as an excellent drug delivery nanoplatform and radiofrequency ablation agent [27]. The bioactive gallic acid (GA) was selected to conjugate with GO and assist in the reduction of GO. The as-prepared gallic acid-reduced graphene oxide (GA-rGO) displayed a good toxic and apoptosis effect on A-498 RCC cells, meanwhile remaining safe to the normal HK-2 cells. Further enhancement of the in vitro therapeutic effect of GA-rGO was achieved by combining radiofrequency ablation. The inhibition percentage of GA-rGO in combination with radiofrequency ablation reached 88.98%, which was significantly higher than that for GA alone (27.54%), GA-rGO alone (35.47%), and radiofrequency ablation alone (52.02%). These results were cheering for functionalized nanomaterials to overcome the limitations in traditional RCC therapy. Jiang et al. constructed a graphene oxide-polydimethylsiloxane (GO-PDMS) milli-capsule controlling drug release for RCC treatment [28]. With the assistance of biocompatible PDMS polymers, the implantable GO-PDMS milli-capsule achieved accurate GO drug release through in vitro NIR irradiation and photo-induced deformation, showing a dosage-dependent RCC inhibition enhancement. In this work, GO with a relatively large size served as the skeleton of the milli-capsule and the NIR-response photothermal transducer, while the encapsulated small GO fragments were efficient drugs for RCC cell proliferation. Recently, Meng's team also reported the therapeutic effect of GO nanomaterials for RCC treatment (Fig. 2) [29,30]. Iron single atoms were modified on GO nanosheets as the active sites and PEGylation was performed to improve the biocompatibility. The obtained iron single atom-graphene oxide (Fe₁-GO) nanomaterial exhibited enhanced cytotoxicity upon the ACHN human RCC cells but maintained tolerable cytotoxicity upon the normal HK-2 and podocyte cells. Further analysis demonstrated that with the well-dispersed iron single atom sites, Fe₁-GO inhibited RCC proliferation by upregulating autophagy in the ACHN cells instead of improving the catalytic generation of reactive oxygen species. In the RCC-bearing mice model, the Fe₁-GO nanomaterial achieved a tumor weight reduction of 89% and good biosafety, validating the efficacy of Fe₁-GO nanomedicine as a promising autophagy inducer for RCC treatment.

  Figure 2

  

  Figure 2.  (a) Schematic illustration of Fe₁-GO nanomedicine for RCC treatment. (b) Aberration-corrected HAADF-STEM image of Fe₁-GO. (c) Cytotoxicity of Fe₁-GO and GO nanosheets on ACHN cells. (d) Cytotoxicity of Fe₁-GO and GO nanosheets on HK-2 cells. (e) Cytotoxicity of Fe₁-GO and GO nanosheets on podocyte cells. (f) Effects of Fe₁-GO nanosheets on autophagy in ACHN cells (*P < 0.05). (g) The evolvement curves of tumor volume for RCC-bearing mice. (h) Final tumor weight by the end of the in vivo treatment (*P < 0.05, ****P < 0.0001). Reproduced with permission [29]. Copyright 2024, Elsevier B.V.

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  2.2 Metal nanomaterials

  Metal nanomaterials with antitumor properties have attracted particular attention in cancer treatment [31,32]. The flexible physical and chemical features of metal nanomaterials allow the precise control of size, morphology, and surface modification. Additionally, the booming green synthesis of metal nanomaterials in combination with natural compounds offers opportunities to improve biocompatibility and reduce cytotoxicity. Some metal nanomaterials could also interact with the external field, which favors the targeting and tracking of the process of treatment.

  Gold nanoparticles were widely reported metal nanomaterials in RCC treatment due to the abovementioned advantages. Pedro et al. investigated the efficacy of gold nanoparticles (CYT-6091, CytImmune Sciences, Inc.) for radiofrequency ablation treatment in a translational renal tumor model [33]. The gold nanoparticles coated with polyethylene glycol and tumor necrosis factor–α successfully minimized the incomplete kill zone in the thermal lesion during radiofrequency ablation thereby enlarging the volume of cell death. Mahmoudi's group also reported radiofrequency radiation in combination with gold nanoparticles as a promising nephrectomy alternative [34]. A significant inhibition in HEK cell survival was observed in the radiofrequency exposure group with the assistance of gold nanoparticles. Lee and coworkers manufactured a drug delivery platform based on gold nanorods encapsulated in human serum albumin protein (HSA-AuNR) [35,36]. After loading sorafenib (SRF) as the tyrosine kinase inhibitor for RCC treatment, the capability of the nanoplatform (HSA-AuNR-SRF) was first verified in vitro using a 786-O RCC cell line. The photothermal effect of gold nanorods enabled the nanoplatform to reach the target temperature of >50 ℃ quickly under NIR laser irradiation, inducing a significant decrease in RCC cell viabilities compared with the dark controls. Accompanied by the photothermal ablation, the irradiation-triggered release of SRF further enhanced the cytotoxicity relative to the group of HSA-AuNR under irradiation. The findings were subsequently validated in vivo resulting in a kill rate of 100% for RCC cells in the group combining HSA-AuNR-SRF and laser irradiation, which was the most pronounced necrosis in all the groups. Inspired by the antitumorigenic property of Curcuma wenyujin, Li et al. biosynthesized gold nanoparticles using this plant as the precursor and evaluated the anticancer effect on the A-498 RCC cell line [37]. The outcome satisfied the distinctive characteristics of a potential therapeutic drug. The biosynthesized gold nanoparticles increased the expression of apoptotic proteins while suppressing that of the antiapoptotic ones, therefore leading to apoptosis in the RCC cells. Paik et al. reported an anti-cancer drug delivery system (αS-AuNP) using gold nanoparticle (AuNP) microcapsules with α-synuclein protein (αS), which was light-responsive and protease-sensitive [38]. Under cancer-related stimuli, hydrophobic cargo loaded in the αS-AuNP microcapsules was selectively released, demonstrating potential in improving the pharmacokinetic profile of the hydrophobic drugs. This system was employed to deliver the hypoxia-inducible factor 2α antagonist (PT2385) in the RCC-bearing mouse model. The in vitro efficacy of the αS-AuNP system delivering PT2385 was comparable to the outcome received from the direct PT2385 treatment group, indicating the reactivity of PT2385 in the system. Further experiments in the mouse model suggested a more significant reduction of tumor size for the αS-AuNP-PT2385 microcapsules than for PT2385-treated alone. Thus, the system not only effectively transported the hydrophobic drugs suppressing mRNA expression but also exhibited a photothermal effect upon irradiation that helped to strengthen the therapeutic effect. Driven by the good therapeutic effect of gold nanoparticles, Dai et al. examined the toxicity and correlated mechanism of gold nanoparticles with different sizes in RCC treatment, moving a step closer toward biomedical application [39]. The results suggested that in HK-2 cells, the activity of Akt and mTOR signaling pathways was reduced during gold nanoparticle treatment, upregulating LC3-II expression and thereby inducing autography to resist the injury. For 786-O RCC cells treated by gold nanoparticles, the increased expression of Caspase 3 led to apoptosis while the PI3K/Akt/mTOR signaling pathways were downregulated. Thus, RCC-specific cytotoxicity could be induced by the gold nanoparticles, whereas the normal HK-2 cells could survive through autography (Fig. 3). Also, this work revealed that the diameter difference (5 nm and 200 nm) of gold nanoparticles did not obviously affect the cytotoxicity and cell apoptosis, offering opportunity to screen the nanoparticles with desired size for RCC therapy.

  Figure 3

  

  Figure 3.  Schematic representation of the effects of gold nanoparticles (5 and 200 nm) in HK-2 cells and 786-O cells. Copied with permission [39]. Copyright 2020, Future Medicine Ltd.

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  For other metal nanoparticles, zinc has attracted great attention due to its critical role in immune function and apoptosis [40,41]. Haroun et al. investigated the antitumor activity of the biosynthesized zinc nanoparticles in the ferric-nitrilotriacetate-induced RCC rat model [42]. Zinc nanoparticles were prepared with the addition of Agaricus bisporus mushroom. For the treatment of RCC induced by ferric nitrilotriacetate (Fe-NTA), zinc nanoparticles could ameliorate the oxidative stress, improve apoptosis, and reduce tumor cell infiltration, displaying excellent therapeutic effect in comparison with the Fe-NTA alone and normal control groups. Therefore, zinc nanoparticles were considered as a potential nanomedicine against RCC.

  2.3 Oxide nanomaterials

  Oxide nanomaterials are also promising candidates for RCC therapy. The multifunctionality of oxide nanomaterials (magnetic property, enzyme-mimic activity, etc.) endows its cooperation with state-of-the-art technologies for RCC treatment. Moreover, the extensive and systematic research of oxide nanomaterials in catalysis also facilitates biomedical assessment and applications.

  The tunable pore size, large surface area, and high pore volume of mesoporous silica nanoparticles demonstrate its capability as a multifunctional carrier in cancer therapy. Gao's group successfully loaded lonidamine (LND, a thermosensitive mitochondrial metabolism-interfering drug) and polydopamine (PDA, a photothermal agent) in mesoporous silica nanoparticles (MSNs) and then embedded the nanoparticles with RCC membranes [43]. A systematic investigation was performed to analyze the LND release dynamics and NIR responsiveness for LND-loaded MSNs (MLD), LND-loaded MSNs-PDA (MLP), and RCC membrane-coated MLP (MLP@M). The MLP@M nanosystem was validated both in vitro and in vivo with improved tumor-suppressing and anti-proliferation activities. Attributed to the pH-sensitive polydopamine, the MLP@M nanosystem could target the RCC lesions and trigger efficient intracellular LND release, integrating combined chemotherapy and photothermal therapy (PTT) under NIR irradiation. The therapeutic efficiency of combined therapy in vivo highlighted that 80% of mice did not relapse after treatment (Fig. 4). Chen et al. reported a novel chemo-sonodynamic therapy based on mesoporous silica nanomaterials [44]. Curcumin as a potential sonosensitizer was confined in hollow mesoporous silica nanoparticles and then encapsulated in the injectable thermosensitive hydrogel. After intratumoral injection, the nanoplatform transformed into an elastic gel matrix. High tissue-penetrating irradiation of ultrasound could trigger the release and activation of curcumin for chemo-sonodynamic therapy. Reactive oxygen species generated in this way effectively inhibit the residual xenograft RCC tumor after thermal ablation. The therapeutic effect of the nanoplatform could also be tracked conveniently by 3D contrast-enhanced ultrasound imaging. The nanoplatform provided a promising alternative to visually track the progress during chemo-sonodynamic RCC therapy.

  Figure 4

  

  Figure 4.  (a) In vitro drug release profiles at pH 7.4 and pH 5.0 (mean ± SD, n = 3). (b) NIR thermal images of MLD, MLP, and MLP@M under an 808 nm laser irradiation for different time. (c) Tumor growth variations of mice, mean ± SD (n = 5), **P < 0.01, ***P < 0.001, ****P < 0.0001. (d) Representative images of dissected tumors of each group on the 17th day. (e) Mechanism of MLP@M. Reproduced with permission [43]. Copyright 2021, Elsevier Inc.

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  Titanium oxide (TiO₂) nanomaterials have been widely investigated as potential photosensitizers in photodynamic therapy since the discovery of their photocatalytic activity. Cheng et al. reported a facile approach to preparing TiO₂ nanobelt-graphene (TiO₂/GR) composite [45]. In vitro treatment revealed the significant photothermal suppression of RCC cell viability (4.72%) by TiO₂/GR under NIR irradiation, whereas the tumor cell viability for other groups remained above 98%. Xu and coworkers developed a core-shell structured titanium oxide@red phosphorus (TiO₂@RP) nanorods for synergistic photodynamic and photothermal RCC therapy [46]. The decoration of the red phosphorus shell expanded the absorption window of TiO₂ to the NIR region. In response to the penetrated NIR irradiation (808 nm), TiO₂@RP nanorods effectively produced local heat as well as singlet oxygen (¹O₂) for killing 786-O RCC cells via apoptosis but caused limited injury to the normal HK-2 cells.

  Zinc oxide (ZnO) nanoparticles with potential cytotoxicity and genotoxicity have also been investigated in RCC therapy [47]. Li et al. found that ZnO nanoparticles would induce ferroptosis in the 786-O RCC cells, thus suppressing RCC cell invasion and migration. The mechanical investigation identified the responsible miR-27a-3p/YAP axis triggered by ZnO nanoparticles during RCC treatment [48]. Zhou et al. also reported the therapeutic effect of ZnO nanoparticles against RCC [49]. Both in vitro and in vivo models demonstrated the inhibition of 786-O RCC cells by ZnO nanoparticles. In-depth analyses found elevated miR-454–3p level and suppressed ACSL4 in RCC cells during the treatment. Despite differences, these works validated the antitumor effect of ZnO nanoparticles against RCC.

  Magnetic nanoparticles (ferroferric oxide as the representative) could be manipulated by external magnetic fields, facilitating field-directed targeting, drug delivery, and biomedical monitoring [50,51]. Shende and Takke reported the delivery of silibinin, an anticancer bioactive component, using magnetic ferroferric oxide (Fe₃O₄) as the nanoplatform [52,53]. Silibinin loaded in the Fe₃O₄ magnetic core was further encapsulated by poly(D,L-lactide-co-glycolic) acid network to improve biocompatibility. The obtained nanocarrier realized sustained in vitro silibinin delivery for 15 days, showing more obvious inhibition on the A-498 RCC cells than the group treated with silibinin alone. In vivo study in mice model also confirmed the biosafety of this nanocarrier.

  Lee et al. reported the toxicological effect of cadmium oxide (CdO) nanoparticles upon normal and renal tumor cells [54]. The dosage-dependent cytotoxicity of CdO nanoparticles emphasized the attention to environmental exposure in related industries.

  Considering that cancer cells require more copper elements than normal ones, Sun's group designed cuprous oxide (Cu₂O) nanoparticles as copper transport regulators and investigated their therapeutic effect against RCC [55]. The in vitro and in vivo results demonstrated that Cu₂O nanoparticles would downregulate the copper chaperone proteins, thus influencing intracellular copper trafficking and inducing endoplasmic reticulum stress for RCC cell apoptosis. In addition, Cu₂O nanoparticles would also recover the sunitinib responsiveness in the sunitinib-resistant RCC cells, facilitating the treatment of acquired drug resistance. This work about copper chaperone proteins and the involved pharmacological effects provided new insights into the interaction between nanomaterials and tumor microenvironments.

  Li et al. fabricated a theranostic nanoplatform taking advantage of Mn²⁺ generation from manganese dioxide (MnO₂) in response to the tumor microenvironment [56]. In the nanoplatform, MnO₂ nanosheets with a high surface area served as the host material, polyethylene glycol (PEG) was decorated on the surface of MnO₂ nanosheet improving the biocompatibility, and osteopontin (OPN) siRNA as a gene-drug was also grafted through the streptavidin bridge. The as-obtained PEG-MnO₂-OPN siRNA nanocomplex could not only be reduced by the high-level glutathione in RCC cells (786-O) and produce Mn²⁺ for MRI contrast enhancement but also realize in situ drug release for gene silencing and achieve effective tumor growth suppression. This tumor microenvironment-activated multifunctional nanoplatform was promising to reduce the side effects and improve the efficacy of RCC therapy.

  Recently, inspired by the high consumption of glucose in tumor tissues, Wang et al. designed a hybrid nanozyme mimicking glucose oxidase for RCC treatment [57]. The nanozyme (denoted as CeO₂@Au-PEG) was constructed by cerium oxide nanorods, further decorated with gold nanoparticles for radiotherapy, and PEGylated for biocompatibility. The peroxidase-mimicking activity of CeO₂@Au-PEG was verified by the decreased pH value and increased concentration of hydrogen peroxide as well as reactive oxygen species. In vitro and in vivo evaluations further confirmed the synergistic effect of CeO₂@Au-PEG and radiotherapy in the RCC model. The combined treatment achieved remarkable RCC inhibition through effective glucose conversion, improved oxidative stress, and enhanced radiosensitization, providing a new strategy for cascade treatment mediated by nanomaterials (Fig. 5).

  Figure 5

  

  Figure 5.  (a) Schematic illustration of the preparation of CeO₂@Au-PEG nanocomposite. (b, c) Evaluation of glucose oxidation by measuring pH values and H₂O₂ concentration. (d) Evaluation of peroxidase-like activities of various CeO₂@Au-PEG concentrations. (e) Viability of RCC cells measured by CCK8 assay after various treatments (Scale bar: 50 µm). (f) The tumor growth curves during different treatments (n = 5). (g) Schematic illustration of ROS generation by CeO₂@Au-PEG in cells. Reproduced with permission [57]. Copyright 2024, Lei and Wang, Dove Medical Press Limited.

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  2.4 Other nanomaterials

  Except for the categories mentioned above, there are also many inorganic nanomaterials arising as potential agents against RCC.

  Kong et al. reported the effects of hydroxyapatite (HAP) nanomaterials on RCC cell apoptosis and invasion [58]. The treatment of HAP nanoparticles significantly restrained the proliferation and invasion of 786-O RCC cells and upregulated the expression of Caspase-12 leading to cell apoptosis.

  Two-dimensional molybdenum diselenide (MoSe₂) with low cytotoxicity is a potential therapeutic candidate for RCC treatment. An's group put forward a facile strategy to prepare carbon-doped MoSe₂ nanoparticles conjugated by bovine serum albumin with good biocompatibility [59]. In vitro tests displayed that the viability of normal kidney cells (HK-2) treated by carbon-doped MoSe₂ nanoparticles remained above 90%, indicating low toxicity. However, for the groups of RCC tumor cells (786-O and ACHN), carbon-doped MoSe₂ nanoparticles showed obvious anti-cancer effects. Mechanism studies implied that the higher uptake ability of RCC cells than the normal cells may be responsible for the therapeutic effect of nanoparticle aggregations.

  Hua and co-workers studied the effect of Oudemansiella raphanipies polysaccharide-decorated selenium nanoparticles (ORPS-SeNPs) on several cancer cell lines [60]. The size-tunable ORPS-SeNPs obtained from facile green synthesis exhibited good storage stability for at least 90 days. While maintaining no obvious cytotoxicity to the normal human mesangial cell, ORPS-SeNPs showed dose-dependent cytotoxicity against RCC cells (786-O) with an IC50 value of 18.88 ± 1.52 mg/L. Systematic in vitro analyses ascribed the potential mechanism to the apoptotic and mitochondria-mediated pathways.

  Targeting the overexpression of DNA-dependent kinase catalytic subunit (DNA-PKcs) in RCC, Shang et al. reported improved ionizing radiation (IR)-induced RCC cell apoptosis by the biocompatible black phosphorous quantum dots (BPQDs) [61]. The combined treatment of 786-O RCC cells through IR and BPQDs resulted in a higher percentage of apoptotic cells than of either monotreatment group, validating the role of BPQDs as highly active radiosensitizers. The analysis of DNA double-strand breaks indicated that the corporation of BPQDs in IR treatment slowed down the nonhomologous end-joining (NHEJ) process. Further investigation verified the interaction between BPQDs and DNA-PKcs, inhibiting DNA-PKcs-mediated DNA repair and leading to sustained DNA damage under ionizing radiation. Consequently, the combined treatment with both BPQDs and IR led to the most prominent suppression of the RCC tumor volume in the in vivo experiment. This target-based radiosensitization strategy put forward new insights for RCC treatment (Fig. 6).

  Figure 6

  

  Figure 6.  (a) The percentage of AnnexinV-positive apoptotic cells in flow cytometry plots (*P < 0.05, BRQDs + IR versus BPQDs and IR monotreatment groups). (b) Repair ability of DNA DSBs (more than 100 cells were counted, three independent assays). (c) Representative comet images of different groups of cells. (d) Suppressive effects of BPQDs on NHEJ repair (Nu7441 was adopted as a positive control). (e) Immunoblot showing DNA-PKcs pS2056 levels in BPQDs-treated or control 786-O cells at 30 min post 10 Gy IR. (f) Number of DNA-PKcs-pSer2056 foci per cell at the indicated time points post-IR (***P < 0.001). (g) Tumor growth curves of the 786-O tumor-bearing mice treated by PBS, IR, BPQDs, and IR + BPQDs (*P < 0.05, ***P < 0.001). (h) Tumor tissues from mice at the termination of the experiments. Copied with permission [61]. Copyright 2022, the authors, MDPI.

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  3. Conclusion and perspectives

  Throughout the advances above, the application of inorganic nanomaterials in RCC treatment has been widely explored and displayed promising curative effects (Fig. 7 and Table 1). In addition, nanosystems including liposomes, polymers, and nanobubbles have also been investigated in RCC therapy. Certainly, the advantages of inorganic nanomaterials lay the foundation for its role as one of the most critical components of future advanced RCC therapeutic systems. The function of inorganic nanomaterials in RCC therapy consists mainly of (a) drug delivery, in detail, the sufficient specific surface area and tunable pore structure contribute to the improved drug loading and efficient delivery; (b) external field responsiveness, specifically, the physical characteristics are accountable to the photothermal effect, acoustic response, magnetic resonance, etc.; (c) microenvironment responsiveness, of which the chemical and/or catalytic activity would trigger cascade biochemical process in cell/tissue microenvironment. Integrating the distinctive features of nanomaterials and further optimizing the well-established RCC therapy represents a key developing direction for the clinical application of nanomaterials. Depending on the treatment cycle, nanomaterial-mediated radiofrequency ablation has the potential to develop into a new minimally invasive surgical approach. Meanwhile, nanomaterial-mediated sonodynamic and magnetothermal therapies may serve as periodic medical interventions. These therapeutic approaches, including but not limited to those aforementioned, exhibit profound potential and will also achieve clinical application with the development of nanomaterials.

  Figure 7

  

  Figure 7.  Schematic illustration of advanced nanomaterial-based RCC therapy.

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  Table 1

  

  Table 1.  The application of inorganic nanomaterials in RCC treatment.

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  Category	Material	Payload	Role	Finding	Ref.
  Carbon nanomaterials	N-doped MWCNTs	/	Heat transducers for photoablation	Effectivye heat transduction and cellular cytotoxicity depend on nanotube length	[24]
  	Pluronic F127-stabilized MWCNTs	/	Heat transducers for photoablation	Complete ablation of tumors and a >3.5-month durable remission in 80% of mice	[25]
  	GO/BSA-Gd2O3	AS1411-DOX	Specific drug delivery and MRI of RCC cells in vitro and in vivo	Enhanced cytotoxicity toward 786-O renal carcinoma cells, but with fewer side effects on normal cells	[26]
  	GA-rGO	/	Radiofrequency ablation agent	Selectively targeted proliferating and toxic effect to the kidney (A-498) tumor cells and compatible with normal HK-2 cell lines	[27]
  	GO-PDMS	GO fragments	Drug delivery and NIR-response photothermal transducer	Accurate drug release by photo-induced deformation and in-vitro NIR manipulation. Inhibiting ccRCC cell proliferation in a GO-concentration-dependent manner	[28]
  	Fe1-GO	/	Autophagy upregulator	Inhibiting ACHN cells by upregulating autophagy instead of catalytic ROS generation	[29]
  Metal nanomaterials	Au nanoparticles (CYT-6091)	/	Radiofrequency ablation agent	Increasing the size of the complete cell death zone and minimizing the incomplete cell death zone within the thermal lesion	[33]
  	Au nanoparticles	/	Radiofrequency ablation agent	A significant inhibition in HEK cell survival	[34]
  	HSA-Au nanorods	SRF	Drug delivery and photothermal ablation agent	Reliably and consistently achieving target temperatures >50 ℃ and resulting in significant cell death of RCC 786-O when irradiated	[35,36]
  	Biosynthesized Au nanoparticles	/	Apoptosis inducer	Increasing the apoptotic Caspase 3,9, Bid, and Bad, and decreasing the antiapoptotic protein Bcl-2, and Bcl-xl expressions	[37]
  	αS-Au nanoparticles	PT2385	Drug delivery and photothermal agent	Significantly reducing the tumor volume and Ki-67 scores in the A-498 xenograft mouse model	[38]
  	Au nanoparticles	/	Apoptosis inducer	Prompting apoptosis and inhibiting proliferation, while activating autophagy to protect HK-2 cells from AuNPs induced cytotoxicity	[39]
  	Biosynthesized Zn nanoparticles	/	Antioxidant and apoptosis inducer	Ameliorating the oxidative stress induced by Fe-NTA, reducing tumor cell infiltration, and enhancing tumor cell apoptosis	[42]
  Oxide nanomaterials	m-SiO2 nanoparticles-polydopamine	Lonidamine	Drug delivery and photothermal agent	Presenting a pH-sensitive release behavior, achieving enhanced antiproliferation and tumor-suppressing abilities with good biocompatibility	[43]
  	Hollow m-SiO2 nanoparticles	Curcumin	Drug delivery, sonodynamic, and thermal ablation agent	Integrating the on-demand and controlled drug-releasing capability and ROS generation capacity together under US irradiation	[44]
  	TiO2/Graphene	/	Photothermal agent	RCC cell viability decreased sharply to 4.72% in the NIR window	[45]
  	TiO2/Red phosphorus	/	Photodynamic and photothermal agent	Producing local heat and ROS to kill ccRCC cells and causing low injury to normal kidney cells	[46]
  	ZnO nanoparticles	/	Ferroptosis inducer	Down-regulating YAP expression by inducing miR-27a-3p	[48]
  	ZnO nanoparticles	/	miRNA regulator	Elevating the level of miR-454–3p and subsequently suppressing ACSL4 in RCC cells	[49]
  	Fe3O4-PLGA nanoparticles	Silibinin	Drug delivery	Sustained drug delivery for 15 days and better cytotoxicity against human kidney cancer cells (A-498) than silibinin alone	[52,53]
  	Biosynthesized CdO nanoparticles	/	Toxicological effect	Significant cell growth inhibition in a dose-dependent manner, Higher inhibition in the cancer cells than the normal cells	[54]
  	Cu2O nanoparticles	/	Cu transportation disrupter	Regulating the ATOX1 and CCS in RCC cells and promoting the accumulation of intracellular calcium and ROS	[55]
  	PEG-MnO2 nanoplates	Osteopontin siRNA	Specific drug delivery and MRI of RCC cells in vitro and in vivo	The reduction of PEG-MnO2 nanoplates by GSH caused the production of Mn2+ ions for T1-weighted MRI and caused structural degradation, enabling the effective release of the gene-targeted drug	[56]
  	CeO2@Au-PEG	/	Nanozyme and radiosensitizer	Depleting glucose and enhancing oxidative stress through ROS production under ionizing irradiation	[57]
  Other nanomaterials	HAP nanoparticles	/	Apoptosis inducer	Restraining the proliferation and invasion of 786-O RCC cells and upregulating Caspase-12 expression for cell apoptosis	[58]
  	C-MoSe2 particles	/	Anti-canter effect	Higher C-MoSe2 uptake ability of RCC cells than the normal cells	[59]
  	ORPS-Se nanoparticles	/	Apoptosis inducer	Inhibiting 786-O cell proliferation in a time and dose-dependent manner. Inducing 786-O cell apoptosis through an intrinsic pathway	[60]
  	BP quantum dots	/	Radiosensitizer	Inhibiting DNA-PKcs-mediated DNA repair and leading to sustained DNA damage under ionizing radiation	[61]

  Since the concept of nanocatalytic medicine has been put forward by Shi et al., the degree of nanosystem integration is rising with the support of enormous research areas [62]. For the development of highly effective RCC therapeutic nanosystems, we believe several points require ongoing attention.

  To begin with, a comprehensive acknowledgment of the pathogenesis, progression, diagnosis, treatment, and prognosis of RCC is required. An in-depth understanding of RCC is the basis for identifying the therapeutic targets. Fenton reaction in the tumor microenvironment is the most common therapeutic target in nanomaterial-based cancer therapy so far [63–65]. The weak acidity and overexpression of hydrogen peroxide in the tumor cells would be exploited by the nanomaterials to generate reactive oxygen species for tumor control. The relevant research is rooted in the understanding of physiological regulation by oxygen-related enzymes, as well as the extensive study on Fenton reaction in environmental catalysis. As increasing physiological processes are dissected at the atomic/molecular level, growing attention has linked nanomaterial-based cancer therapy to other therapeutic targets, such as autophagy, ferroptosis, glucose metabolism, DNA damage, and so on. The relevant in-depth analysis helps to comprehensively analyze the function of nanomaterials (usually not a single one), and guide the screening and design of nanomaterials.

  Moreover, rational design and precise control of nanomaterials hold the key. Upgrading the design and regulation of nanomaterials concentrated on one or more RCC therapeutic targets is critical to obtaining a good therapeutic effect. In combination with state-of-the-art nanotechnology, the size, morphology, pore structure at the nanoscale, and even defects and active sites at the sub-nanoscale could be finely controlled. As an example, for drug delivery, the synthetic procedure could be adjusted to increase the specific surface area, adjust the pore structure, or modify the dangling groups, thereby broadening the range of drug loading and improving the kinetics of drug release. For tumor microenvironment and external field responsiveness, facet engineering and defect engineering could be employed to enhance the efficiency of the nanomaterials, thus improving their performance in RCC treatment. Unfortunately, almost all the articles are proof-of-concept reports, lacking further regulation and optimization of nanomaterials beyond the preliminary evaluation. Given the complexity of the work involved, the introduction of artificial intelligence and machine learning into the process could be one of the most promising solutions.

  Last but not least, monitoring the life trajectory of nanomaterials as well as evaluating their long-term toxicity throughout the therapy are of great necessity. In addition to displaying the therapeutic effect at the tumor site, nanomaterials affect living organisms from the moment they enter the body. In vivo transport of the nanomaterials includes blood circulation, tumor accumulation, penetration, and cellular internalization [66]. Although the toxicity of nanomaterials could be triggered by external field-guided activation or by recognizing the characteristics in RCC cells, the prolonged presence of nanomaterials in the body during RCC treatment still raises potential implications for physiological function. After the therapy, the nanomaterials would leave the organism through metabolism, excretion, and other ways. Therefore, developing advanced tracer technology to monitor the track of nanomaterials for their absorption, distribution, metabolism, and excretion processes is the final piece of the puzzle before clinical application [67]. These tracks are also important feedbacks for the design and refinement of nanomaterials. Of course, the renal clearable and biodegradable nanomaterials are attractive, whose facile clearance after RCC therapy would shorten the retention and thus lead to a more ideal prognosis.

  Overall, despite the great potential of nanomaterial-based RCC therapies, the development of related fields remains in its infancy. Much more effort should be devoted before this strategy is widely acceptable and clinically applied. Deeper collaboration between nephrologists and nanotechnologists is urgent, to clarify concerns including but not limited to the issues above, and provide a smarter and more effective diagnosis and treatment platform for RCC patients.

  Declaration of competing interest

  The authors declare that they have no competing interests.

  CRediT authorship contribution statement

  Yuanyi Zhou: Writing – original draft, Investigation. Lili Wang: Writing – review & editing, Project administration, Investigation. Li Chen: Investigation. Qingbing Zha: Investigation. Yu Meng: Writing – review & editing, Project administration, Funding acquisition. Mingshan Zhu: Writing – review & editing, Project administration.

  Acknowledgments

  The authors thank the financial support from the National Natural Science Foundation of China (No. 82270756), the Basic and Applied Basic Research Foundation of Guangdong Province, China (Nos. 2414050006150, 2024A1515011405), the Science and Technology Project of Guangzhou, China (No. 202102010133), the Science and Technology Project of Heyuan, China (Nos. 230510171473346, 230510171473347), and the Medical Joint Fund of Jinan University.

  
  
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• 

  Figure 1  Overview of inorganic nanomaterials for RCC treatment.

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  Figure 2  (a) Schematic illustration of Fe₁-GO nanomedicine for RCC treatment. (b) Aberration-corrected HAADF-STEM image of Fe₁-GO. (c) Cytotoxicity of Fe₁-GO and GO nanosheets on ACHN cells. (d) Cytotoxicity of Fe₁-GO and GO nanosheets on HK-2 cells. (e) Cytotoxicity of Fe₁-GO and GO nanosheets on podocyte cells. (f) Effects of Fe₁-GO nanosheets on autophagy in ACHN cells (*P < 0.05). (g) The evolvement curves of tumor volume for RCC-bearing mice. (h) Final tumor weight by the end of the in vivo treatment (*P < 0.05, ****P < 0.0001). Reproduced with permission [29]. Copyright 2024, Elsevier B.V.

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  Figure 3  Schematic representation of the effects of gold nanoparticles (5 and 200 nm) in HK-2 cells and 786-O cells. Copied with permission [39]. Copyright 2020, Future Medicine Ltd.

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  Figure 4  (a) In vitro drug release profiles at pH 7.4 and pH 5.0 (mean ± SD, n = 3). (b) NIR thermal images of MLD, MLP, and MLP@M under an 808 nm laser irradiation for different time. (c) Tumor growth variations of mice, mean ± SD (n = 5), **P < 0.01, ***P < 0.001, ****P < 0.0001. (d) Representative images of dissected tumors of each group on the 17th day. (e) Mechanism of MLP@M. Reproduced with permission [43]. Copyright 2021, Elsevier Inc.

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  Figure 5  (a) Schematic illustration of the preparation of CeO₂@Au-PEG nanocomposite. (b, c) Evaluation of glucose oxidation by measuring pH values and H₂O₂ concentration. (d) Evaluation of peroxidase-like activities of various CeO₂@Au-PEG concentrations. (e) Viability of RCC cells measured by CCK8 assay after various treatments (Scale bar: 50 µm). (f) The tumor growth curves during different treatments (n = 5). (g) Schematic illustration of ROS generation by CeO₂@Au-PEG in cells. Reproduced with permission [57]. Copyright 2024, Lei and Wang, Dove Medical Press Limited.

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  Figure 6  (a) The percentage of AnnexinV-positive apoptotic cells in flow cytometry plots (*P < 0.05, BRQDs + IR versus BPQDs and IR monotreatment groups). (b) Repair ability of DNA DSBs (more than 100 cells were counted, three independent assays). (c) Representative comet images of different groups of cells. (d) Suppressive effects of BPQDs on NHEJ repair (Nu7441 was adopted as a positive control). (e) Immunoblot showing DNA-PKcs pS2056 levels in BPQDs-treated or control 786-O cells at 30 min post 10 Gy IR. (f) Number of DNA-PKcs-pSer2056 foci per cell at the indicated time points post-IR (***P < 0.001). (g) Tumor growth curves of the 786-O tumor-bearing mice treated by PBS, IR, BPQDs, and IR + BPQDs (*P < 0.05, ***P < 0.001). (h) Tumor tissues from mice at the termination of the experiments. Copied with permission [61]. Copyright 2022, the authors, MDPI.

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  Figure 7  Schematic illustration of advanced nanomaterial-based RCC therapy.

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  Table 1.  The application of inorganic nanomaterials in RCC treatment.

  Category	Material	Payload	Role	Finding	Ref.
  Carbon nanomaterials	N-doped MWCNTs	/	Heat transducers for photoablation	Effectivye heat transduction and cellular cytotoxicity depend on nanotube length	[24]
  	Pluronic F127-stabilized MWCNTs	/	Heat transducers for photoablation	Complete ablation of tumors and a >3.5-month durable remission in 80% of mice	[25]
  	GO/BSA-Gd2O3	AS1411-DOX	Specific drug delivery and MRI of RCC cells in vitro and in vivo	Enhanced cytotoxicity toward 786-O renal carcinoma cells, but with fewer side effects on normal cells	[26]
  	GA-rGO	/	Radiofrequency ablation agent	Selectively targeted proliferating and toxic effect to the kidney (A-498) tumor cells and compatible with normal HK-2 cell lines	[27]
  	GO-PDMS	GO fragments	Drug delivery and NIR-response photothermal transducer	Accurate drug release by photo-induced deformation and in-vitro NIR manipulation. Inhibiting ccRCC cell proliferation in a GO-concentration-dependent manner	[28]
  	Fe1-GO	/	Autophagy upregulator	Inhibiting ACHN cells by upregulating autophagy instead of catalytic ROS generation	[29]
  Metal nanomaterials	Au nanoparticles (CYT-6091)	/	Radiofrequency ablation agent	Increasing the size of the complete cell death zone and minimizing the incomplete cell death zone within the thermal lesion	[33]
  	Au nanoparticles	/	Radiofrequency ablation agent	A significant inhibition in HEK cell survival	[34]
  	HSA-Au nanorods	SRF	Drug delivery and photothermal ablation agent	Reliably and consistently achieving target temperatures >50 ℃ and resulting in significant cell death of RCC 786-O when irradiated	[35,36]
  	Biosynthesized Au nanoparticles	/	Apoptosis inducer	Increasing the apoptotic Caspase 3,9, Bid, and Bad, and decreasing the antiapoptotic protein Bcl-2, and Bcl-xl expressions	[37]
  	αS-Au nanoparticles	PT2385	Drug delivery and photothermal agent	Significantly reducing the tumor volume and Ki-67 scores in the A-498 xenograft mouse model	[38]
  	Au nanoparticles	/	Apoptosis inducer	Prompting apoptosis and inhibiting proliferation, while activating autophagy to protect HK-2 cells from AuNPs induced cytotoxicity	[39]
  	Biosynthesized Zn nanoparticles	/	Antioxidant and apoptosis inducer	Ameliorating the oxidative stress induced by Fe-NTA, reducing tumor cell infiltration, and enhancing tumor cell apoptosis	[42]
  Oxide nanomaterials	m-SiO2 nanoparticles-polydopamine	Lonidamine	Drug delivery and photothermal agent	Presenting a pH-sensitive release behavior, achieving enhanced antiproliferation and tumor-suppressing abilities with good biocompatibility	[43]
  	Hollow m-SiO2 nanoparticles	Curcumin	Drug delivery, sonodynamic, and thermal ablation agent	Integrating the on-demand and controlled drug-releasing capability and ROS generation capacity together under US irradiation	[44]
  	TiO2/Graphene	/	Photothermal agent	RCC cell viability decreased sharply to 4.72% in the NIR window	[45]
  	TiO2/Red phosphorus	/	Photodynamic and photothermal agent	Producing local heat and ROS to kill ccRCC cells and causing low injury to normal kidney cells	[46]
  	ZnO nanoparticles	/	Ferroptosis inducer	Down-regulating YAP expression by inducing miR-27a-3p	[48]
  	ZnO nanoparticles	/	miRNA regulator	Elevating the level of miR-454–3p and subsequently suppressing ACSL4 in RCC cells	[49]
  	Fe3O4-PLGA nanoparticles	Silibinin	Drug delivery	Sustained drug delivery for 15 days and better cytotoxicity against human kidney cancer cells (A-498) than silibinin alone	[52,53]
  	Biosynthesized CdO nanoparticles	/	Toxicological effect	Significant cell growth inhibition in a dose-dependent manner, Higher inhibition in the cancer cells than the normal cells	[54]
  	Cu2O nanoparticles	/	Cu transportation disrupter	Regulating the ATOX1 and CCS in RCC cells and promoting the accumulation of intracellular calcium and ROS	[55]
  	PEG-MnO2 nanoplates	Osteopontin siRNA	Specific drug delivery and MRI of RCC cells in vitro and in vivo	The reduction of PEG-MnO2 nanoplates by GSH caused the production of Mn2+ ions for T1-weighted MRI and caused structural degradation, enabling the effective release of the gene-targeted drug	[56]
  	CeO2@Au-PEG	/	Nanozyme and radiosensitizer	Depleting glucose and enhancing oxidative stress through ROS production under ionizing irradiation	[57]
  Other nanomaterials	HAP nanoparticles	/	Apoptosis inducer	Restraining the proliferation and invasion of 786-O RCC cells and upregulating Caspase-12 expression for cell apoptosis	[58]
  	C-MoSe2 particles	/	Anti-canter effect	Higher C-MoSe2 uptake ability of RCC cells than the normal cells	[59]
  	ORPS-Se nanoparticles	/	Apoptosis inducer	Inhibiting 786-O cell proliferation in a time and dose-dependent manner. Inducing 786-O cell apoptosis through an intrinsic pathway	[60]
  	BP quantum dots	/	Radiosensitizer	Inhibiting DNA-PKcs-mediated DNA repair and leading to sustained DNA damage under ionizing radiation	[61]

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