The different valence states of iron have been exploited to develop nanomaterials that act as FINs to kill cancer cells. In the zero-valent iron NP (ZVI NPs)–sensitive cancer cells, Fe⁰ could be oxidized to Fe²⁺ (Huang et al., 2019). The increased iron induced intracellular ROS surge via Fenton reaction, followed by the accumulation of mitochondrial LPOs. The monodispersed ferrihydrite NPs were synthesized and demonstrated the light-triggered Fe²⁺ generation at the tumor sites (Yang, Y. et al., 2021). Ferrihydrite NPs, 20∼30 nm, could release a large amount of Fe²⁺ to promote the iron/ROS-related irreversible DNA fragmentation and GPX4 inhibition under a common blue light illumination. In addition, it simultaneously induced polarization of the tumor-associated macrophage (TAM) from the tumor-promoting M2 phenotype to the tumor-killing M1 type, which concomitantly inhibited the tumor growth and prevented lung metastasis under illumination in vivo. The sulfasalazine and disulfide-bridged levodopa (DSSD) assembled as sulfasalazine@DSSD that could chelate Fe²⁺ to form the prodrug nanosystem sulfasalazine–Fe²⁺@DSSD (Xin et al., 2021). The disulfide bonds could consume GSH in tumor cells, triggering the leakage of sulfasalazine and Fe²⁺. Fe²⁺ induced ferroptosis via the Fenton reaction, and this was enhanced by the presence of sulfasalazine to improve the therapeutic efficacy. In another system, doxorubicin (DOX) was chelated with Fe²⁺, yielding Fe²⁺-DOX, which was condensed with calcium-containing precursors to form amorphous calcium carbonate (ACC)–encapsulated Fe²⁺-DOX cores via a one-step synthetic approach (Figure 4) (Xue et al., 2020). The nanoplatform was simultaneously modified with matrix metalloproteinase-2 (MMP-2)–sheddable PEG and folic acid (FA) to achieve circulation stability and targeting capability. The therapeutic nanomaterial could release Fe²⁺ that produced H₂O₂ and DOX that amplified the effect of Fe²⁺ under a pH-triggered and self-regulated manner.

Recently, Cui et al. prepared a nanoenzyme in which Fe³⁺ was substantially reserved in the polypyrrole NPs (FePPy NPs) (Cui et al., 2021). The FePPy NPs generated hydroxyl radicals (•OH) by the degradation of H₂O₂ to induce ferroptosis. Upon irradiation, the FePPy NPs induced low-temperature PTT, which accelerated the Fenton reaction and enhanced ferroptosis and photoacoustic imaging (PAI) in vitro and in vivo. In addition, nanomaterials based on Fe³⁺ and tannic acid (TA) with the DOX-loaded dendrimers could combat multidrug resistance (MDR) in cancer cells via the apoptosis/ferroptosis pathway (Guo et al., 2019). The DOX-induced apoptosis elevated the intracellular ROS levels, thus sensitizing cancer cells to ferroptosis. The efficiency of CDT, in which H₂O₂ is decomposed into toxic •OH in tumor cells, was improved. Chen H. et al. reported a nanodrug delivery system based on TA, Pluronic F-68, and Fe³⁺ (Chen, H. et al., 2021). DOX, Pluronic F-68, and TA were first assembled to form DOX@Pluronic F-68/TA by π–π interactions and hydrophobic bonds. Subsequently, Fe³⁺ was introduced onto the surface of DOX@Pluronic F-68/TA to form DOX@Pluronic F-68/TA/Fe³⁺ via elaborate coordination interactions. The nanodrug DOX@Pluronic F-68/TA/Fe³⁺ efficiently targeted the tumor and primely suppressed tumor growth. In addition, the hollow mesoporous silica NP (MSNP)–loaded ferrate and DOX were followed by incorporating n-heneicosane (Fu et al., 2021). The mild hyperthermia induced by US initiated the phase change of n-heneicosane and enabled the co-release of ferrate and DOX. The ferrate then reacted with H₂O to form H₂O₂, which released O₂, thus causing TME-independent reoxygenation and downregulation of the expression of hypoxia-inducible factor 1α and MDR gene/transporter P-glycoprotein in tumor cells. Overall, the cooperation of chemotherapy and FBT resulted in enhanced suppression of hypoxic osteosarcoma growth in vivo.

Dopamine can be used to load hydrophobic drugs and metal ions due to its aromatic rings and catechol groups (Cheng et al., 2019). Furthermore, polydopamine (PDA) shows strong absorption in the NIR region at approximately 808 nm and can efficiently convert the light energy into thermal energy (Rahim et al., 2019;Yamagishi et al., 2019). PDA nanosubstrates could efficiently load Fe²⁺ and β-lapachone, which initiated ferroptosis in the tumor cells subjected to NIR illumination (Xue et al., 2021). Crucially, cellular hyperthermia was generated by PDA nanostructures under NIR irradiation and triggered the release of Fe²⁺. The NIR-enabled PTT also activated heat shock response and upregulated NADPH: quinone oxidoreductase protein (NQO1) via the heat shock protein 70 (HSP70)/NQO1 axis to promote bioreduction of β-lapachone and boost the intracellular H₂O₂ levels to facilitate the Fe²⁺-dependent lipid peroxidation, while minimizing the potential damage to normal tissues (Figure 5) (Xue et al., 2021). The Fe²⁺ and Fe³⁺ also could be loaded into the core of the ultrasmall PEG-modified PDA NPs (UPDA-PEG NPs, 8.4 nm), thus yielding a novel ferroptosis agent (Chen et al., 2019). Seventy percent of the iron ions could be released at pH 5.0, suggesting applications in the acidic TME. The ferroptosis induced by UPDA-PEG@Fe²⁺ NPs was dependent on ROS, whereas UPDA-PEG@Fe³⁺ NPs induced LPO-dependent ferroptosis. In another research, DOX was loaded onto the PDA NPs to achieve a synergistic effect (Nieto et al., 2021). The pH determined the Fe³⁺ state and the selectivity and therapeutic activity of the resultant Fe³⁺-loaded PDA NPs. Furthermore, the antitumor activity could be enhanced by DOX, which also increased ROS production in the cancer cells, and PDA NPs with different concentrations of Fe³⁺ and drugs could be tailor-synthesized and administered depending on the therapeutic need. The Fe³⁺ and the catechol of dopamine molecules could self-polymerize Fe³⁺-PDA cores with an Fe loading efficiency of 5.3% (Chen et al., 2020). Subsequently, the hyaluronic acid (HA) cross-linked cisplatin shells were constructed onto the Fe³⁺-PDA cores, and the core-shell nanomaterial was highly sensitive to an acidic or reductive TME, while its disassembly led to the continuous release of cisplatin and Fe³⁺. The cisplatin could enhance ferroptosis via activating the NADPH oxidases (NOXs) and suppressing GPX4. Thus, the core-shell nanomaterial provided a new antitumor strategy for synergistic chemotherapy/FBT/PTT with a low dosage.

Iron ions could also be coordinated to some nanomaterials. For example, Jiang Y. et al. reported a hybrid semiconducting nanozyme (HSN) possessing high photothermal (PT) conversion efficiency and NIR-II PAI-guided PTT/FBT (Jiang, Y. et al., 2020). HSN comprised the amphiphilic semiconducting polymer as a PT converter, PA emitter, and iron-chelating Fenton catalyst. Upon NIR-II irradiation, HSN induced PT transduction, which triggered PTT and potentiated the Fenton reaction. Furthermore, •OH transformed HSN to approximately 1.7 nm–sized fragments. The noninvasive therapy possesses several advantages, such as deep ablation, reduced expression of metastasis-related proteins, and inhibition of distant metastasis. Recently, artemisinin and its derivatives have been investigated as potential FINs for cancer treatment. The nanocarrier-containing artemisinin was based on TA and Fe²⁺ coated on the zeolitic imidazolate framework-8 (ZIF-8) (Li, Z. et al., 2021). After 10 h, 59% artemisinin was released from TA-Fe²⁺/artemisinin@ZIF-8 in pH 5.0. The intracellular ROS production and GPX4 inhibition could lead to suppression of triple-negative breast cancer growth.

The nanoscale MOFs formed by Fe²⁺ and 2-aminoterephthalic acid (BDC-NH₂) possessed excellent stability and pH-responsive degradation to release Fe²⁺ in the acidic TME, which could catalyze the Fenton reaction and produce considerable quantities of ROS to induce Fe²⁺-mediated ferroptosis (Xu et al., 2020). The perfluoropentane@Fe/Cu-SS MOF is displayed as an effective FIN because it could increase the production of LPO through the Fenton reaction and inhibit the GPX4 that prevents LPO transfer to LOH in the presence of GSH, whereas the Fe³⁺ and Cu²⁺ in the MOF could consume GSH, further inhibiting GPX4 activity. Perfluoropentane@Fe/Cu-SS MOF also enabled T1-weighted magnetic resonance imaging (MRI), US imaging, and PTT (He, H. et al., 2020). Au1Ag24 nanoclusters and Fe³⁺ could be effortlessly assembled in an oil phase and modified by the vesicles of the PEG block grafted polyketal copolymer (PbP). The core-shell cancer theranostic nanomaterial Fe³⁺@Au1Ag24@PbP possessed several excellent multiproperties, including NIR laser/TME co-responsiveness and PAI/PT imaging-guided PTT/PDT/FBT both in vitro and in vivo (Cheng, H. et al., 2021). In addition, the iron-chelated hybrid polymeric NPs comprising Fe³⁺ and an amphiphilic semiconducting complex have been reported, in which these components acted as PT transducers and Fe³⁺ chelators, respectively (He, S. et al., 2020). In the acidic TME, Fe³⁺ was released to generate •OH; in addition, local heat was generated under the NIR laser irradiation to enhance the Fenton reaction and achieve PAI-guided PTT.

The addition of cancer cell membranes to nanomaterials enables homologous targeting and immune escaping capabilities. Wan et al. reported a nanomaterial containing Fe³⁺-based MIL-100 and glucose oxidase (GOx) that catalyzed the degradation of glucose to generate sufficient H₂O₂ for FBT (Wan et al., 2020). When the nanomaterial was obtained by the tumor cells, intracellular GSH triggered the disruption of MOF via reducing Fe³⁺ to release Fe²⁺ and GOx. The nanomaterial exhibited highly effective tumor inhibition and enabled precise collaborative tumor therapy with spatiotemporal controllability. Another MOF nanomaterial loading with GOx and DOX was also coated with the cancer cell membrane (denoted as mFe(SS)/DG) (Figure 6) (Yang, J. et al., 2021). The mFe(SS)/DG system based on Fe³⁺ and disulfide-bearing ligands depleted GSH and suppressed GPX4 activity to induce ferroptosis. The increasing ROS facilitated ferroptosis and restrained glycolysis. Thus, immunogenic cell death (ICD) induced by the synergistic effect of ferroptosis and DOX released tumor antigens to trigger antitumor immunity when the inhibition of glycolysis remodeled the tumor immunogenicity and immunosuppressive microenvironment to strengthen the antitumor immunity.

In addition, iron-based MOFs can be loaded with FINs to enhance ferroptosis. For example, MIL88B loaded with RSL3 forced M2 macrophages to increase the glycolytic metabolism (Gu et al., 2021). MIL88B/RSL3 downregulated the expression of M2-associated signaling pathways and activated M1-related signaling. The ferroptosis-strengthened macrophage regulation strategy had great potential for TAM-centered antitumoral applications. In the same year, the surface of MIL-101 (Fe)-loaded sorafenib was modified with an iRGD peptide that could bind to neruopilin-1 receptor yielding a nanodrug that induced ferroptosis of the hepatocellular carcinoma by consuming GSH, decreasing GPX4 expression, and enhancing LPO generation (Liu et al., 2021). Fe³⁺ and TA spontaneously formed a network-like corona onto the sorafenib nanocores that were loaded with methylene blue (Liu et al., 2018). The corona is disrupted in the lysosomal acid environment, whereas TA could reduce Fe³⁺ to Fe²⁺, paving the way for iron redox cycling to produce LPO. Furthermore, the concomitant methylene blue release induced fluorescence recovery, endowing the nanomaterials with multimodal imaging-guided PDT/FBT. In another example, Fe³⁺-containing MOFs loaded with piperlongumine (a FIN) were coated with a transferrin-decorated pH sensitive lipid layer to form the nanodrug (Xu, R. et al., 2021). Crucially, after treatment with this nanoagent, the cellular iron concentration increased dramatically due to the iron-containing MOF, and piperlongumine strengthened the ferroptosis via providing H₂O₂ for the dual induction system.

FePt-based nanomaterials have potential clinical applications in cancer therapy. For example, a ferroptosis nanotheranostic agent was designed by integrating FePt as the core, Eu³⁺-based luminescent molecule, and FA as the targeting molecule (Yue et al., 2018). FePt-based nanomaterials exhibited an excellent MRI, computed tomography (CT), and time-gated luminescence properties in the clinical diagnosis and had excellent capacity to trigger ferroptosis of cancer in vitro and in vivo.

The FePt NPs can also be loaded onto diverse nanomaterials to show their advantages. An acidic responsive nanoagent FePt@MnO@DSPE-PEG-FA NP was successfully constructed for MRI-guided FBT/CDT of cancer (Figure 7) (Yang et al., 2019). It could release active Fe²⁺ to elevate ROS production via the Fenton reaction to induce ferroptosis. In addition, Mn²⁺ could be released from the nanomaterial in the acidic TME and scavenge GSH to enhance the T1/T2-weighted MRI, which could obviously distinguish the solid tumors. Prussian blue (PB) nanocubes were utilized as PT agents, and FePt NPs were loaded onto the surface of the nanocube via in situ reduction (Hu et al., 2020). The surface of the nanocomposite PB@FePt was wrapped with HA and PEG, and the nanoagent PB@FePt–HA-g-PEG served as a multifunctional nanomaterial, enabling CDT/PTT and triple-modal imaging (MRI/CT/PT imaging) capability. Covalent organic polymers (COPs) possess specific surface area and good biocompatibility, making them promising nano delivery carriers (Shi et al., 2019). FePt@COP-FA with excellent PT potential was developed for cancer treatment (Meng et al., 2020). It could efficiently ablate the primary tumors with the presentation of NIR irradiation and release a mass of tumor-associated antigens in situ. With the assistance of anticytotoxic T-lymphocyte antigen-4 (anti-CTLA4), the specific immune response was triggered to suppress the growth of metastatic tumors. In particular, the synergistic therapy could form a valid immunological memory to further restrain tumor relapses. FePt NPs could also be loaded onto polyethylenimine (PEI)-modified ultrathin black phosphorus (BP) nanosheets, and this nanomaterial showed enhanced synergistic PTT/PDT/CDT for targeting primary tumors (Yao et al., 2020). More significantly, combined with the CTLA-4 checkpoint blockade, PTT induced by FePt/BP–PEI–FA could control the growth of both the primary and untreated distant tumor.

IONPs, which have been approved by the FDA, have been widely applied in cancer therapy because they produce ROS via the Fenton reaction.

An innovative local chemotherapy combined with a gene therapy–based IONP was developed as a treatment for patients with glioblastoma (Zhang et al., 2020). The porous structure of IONPs attached -COOH groups and could encapsulate the small interfering RNA (siRNA) targeting GPX4 (siGPX4) and cisplatin. After uptake, the IONPs degraded and released Fe²⁺/Fe³⁺, and the H₂O₂ level increased owing to the activating reduced NOX. Furthermore, the cisplatin destroyed both nuclear and mitochondrial DNA, while siGPX4 restrained GPX4 expression. The manganese-deposited IO (FMO) NPs were loaded with the cisplatin prodrug Pt (IV) to form Pt-FMO, which was modified with PEG to increase colloidal stability (Cheng, J. et al., 2021). FMO released Mn²⁺ and Fe²⁺/Fe³⁺ in the weakly acidic TME, and the Pt (IV) could deplete GSH to generate cisplatin. Mn²⁺ enhanced the ferroptosis induced by Fe²⁺/Fe³⁺ released from FMO, and cisplatin elevated the intracellular H₂O₂ levels, which obviously strengthened ferroptosis via the Fenton reaction. Therefore, the synergism between the ferroptosis induced by FMO and the apoptosis induced by cisplatin resulted in tumor ablation.

Biomimetic magnetic NPs coated with platelets can make the cancer cells sensitize to ferroptosis, generate mild immunogenicity, and improve the response rate of noninflammatory tumors to immunotherapy (Jiang, Q. et al., 2020). Thus, a Fe₃O₄-sulfasalazine@platelet system was designed by using mesoporous magnetic Fe₃O₄ NPs, sulfasalazine, and platelet membranes. Fe₃O₄–sulfasalazine@platelet-mediated ferroptosis could evidently improve the potency of programed cell death 1 (PD-1) and achieve persistent tumor elimination in 4T1 metastatic tumors. Moreover, the Fe₃O₄–sulfasalazine@platelet-mediated ferroptosis also repolarize macrophages from the M2 phenotype to M1 phenotype. The magnetosomes contained Fe₃O₄ magnetic nanoclusters and pre-engineered the leukocyte membranes as the core and shell, and the transforming growth factor-β (TGF-β) inhibitor and PD-1 antibody were, respectively, loaded inside and on the surface of the membrane (Figure 8) (Zhang et al., 2019). The membrane camouflage endowed the nanomaterial with a long circulation time, and the nanocluster core enabled magnetic targeting under MRI guidance. When the nanomaterial reached the tumor site, the cooperation of the TGF-β inhibitor and PD-1 antibody increased the rates of CD4⁺ T/Treg cells, CD8⁺ T/Treg cells, and M1/M2 macrophages to create an immunogenic TME, and the elevated H₂O₂ from M1 polarization enhanced the Fenton reaction. The production of •OH subsequently induced ferroptosis of the cancer cells and the released tumor antigens, thus increasing TME immunogenicity.

IONPs can also be loaded onto or into different nanomaterials. Superparamagnetic IONPs (SPIONPs) are considered excellent carriers to deliver nucleic acid and drug because of the controllable properties, outstanding stability, and easy modification. The sorafenib and ultrasmall SPIONPs (approximately 8.5 nm) were, respectively, loaded onto the mesopores of mesoporous PDA (MDPA) NPs and onto the surface of the MDPA NPs to form sorafenib@MPDA-SPIONP (Guan et al., 2020). The heat generated by the MPDA NPs upon NIR laser irradiation boosted the effect of ferroptosis. Furthermore, the application of moderate heat (45°C) in the presence of the IONPs could significantly suppress the expression of the antioxidative proteins and cause tumor cells to undergo specific lipid metabolism (Xie et al., 2021). By virtue of the IONPs and 1H-perfluoropentane (1H-PFP), a heat-responsive ferroptosis strategy was rationally designed by utilizing a polypeptide-modified, IO-containing nanomaterial that loaded 1H-PFP. The phase transition of 1H-PFP was triggered under 808-nm laser irradiation, which led to the release of IONPs in situ to produce ROS in the TME. The inhibition of GSH synthesis restrained the antioxidant response of tumors due to heat stress. Furthermore, the combined treatments reprogramed the lipid metabolism by generating a large amount of LPO and inducing acyl-CoA synthetase bubblegum family member 1 (ACSBG1)–dependent ferroptosis in the C4-2 tumor model. More recently, the polypeptide vehicle-based theranostics (Pt&IONPs@PP) were self-assembled by mixing poly (L-glutamic acid) (PGA), poly (L-lysine) (PLL), Pt prodrug, and carboxyl-modified IONPs through electrostatic interactions, and the surface of this nanomaterial was modified with PEG (Gao et al., 2020). The acidic TME degraded Pt&IONPs@PP to release Pt drug and Fe²⁺/Fe³⁺. Moreover, Pt&IONPs@PP could induce T2-weighted, MRI-guided chemotherapy/FBT to inhibit cancer cell growth without systemic toxicity in vitro and in vivo.

A nanosystem containing Fe₃O₄ and chlorin E6 (Ce6) was designed for the synergistic cancer therapy (Chen, Q. et al., 2021). The poly (lactic-co-glycolic acid) (PLGA) was used as the shell to load Fe₃O₄ and Ce6, which degraded in the acidic TME and released Fe²⁺/Fe³⁺ and Ce6. The reaction between Fe²⁺/Fe³⁺ and intracellular H₂O₂ produced •OH to induce ferroptosis of tumor cells. The released Ce6 could increase the ROS levels upon laser irradiation to offer PDT, and this boosted the ferroptosis effect in 4T1 tumors. A gel-delivery platform with embedded Au nanorods (AuNRs) and IONPs was reported, the so-called AuNRs&IONPs@Gel, for bladder cancer therapy (Guo, P. et al., 2020). The gel platform was based on a dextran aldehyde that could selectively adhere with the cancer collagen. AuNRs could induce imaging-guided PTT under NIR radiation, and the locally high concentration of IONPs induced ferroptosis. Moreover, TAMs would be repolarized by the IONPs from the M2 phenotype into M1 phenotype to achieve a direct antitumor effect and antigen presentation of dead cells. This process triggered an effective innate and adaptive immune response to protect against tumor rechallenge in the long term. The black hole quencher (BHQ)–based fluorescence ‘off−on’ nanomaterials were self-assembled with chitosan oligosaccharide (CSO), IR780, hexadecane (Hex), magnetic IONPs (MIONPs), and sorafenib to form CSO-BHQ-IR780-Hex/MIONPs/sorafenib (Sang et al., 2019a). BHQ and IR780 were combined via a GSH-responsive ether bond. After uptake, the CSO–BHQ–IR780–Hex NPs collapsed and IR780–Hex anchored the mitochondrial membrane. When NIR irradiation was applied to the NPs, the iron level increased, and the xCT/GSH/GPX4 system was triggered. In addition, a similar nanomaterial (CSO–SS–Cy7–Hex/SPIONP/sorafenib) was developed to overcome the therapy-resistant state of cancer (Sang et al., 2019b). This system could scavenge GSH and increase the concentration of iron and LPO, and the ferroptosis induced by CSO-SS-Cy7-Hex/SPIONP/sorafenib complex defeated MDR, reduced invasion, and limited the metastasis of cancers undergoing the epithelial-to-mesenchymal transition.

The IO-hydroxide (IOOH) nanospindles have been used as MRI contrast agents for cancer diagnosis; thus, a biocompatible H₂S-responsive IOOH nanospindle for colon cancer is developed (Li, Y. et al., 2020). The IOOH nanospindles, synthesized from Fe³⁺ and dopamine and modified by PEG, could efficiently deplete endogenous H₂S via the reduction reaction to inhibit CT26 colon cancer growth. Crucially, the overproduction of H₂S drove a cascade reaction producing FeS; thus, this system could be used for NIR-responsive PTT and Fe²⁺-induced ferroptosis.

Ferrocene (Fc) is a stable organic transition metal compound that can produce ROS under physiological condition, and thus, is a potential adjuvant to enhance the therapeutic effect of chemotherapy drugs (Patra and Gasser, 2017). As known to all, the iron in Fc is Fe²⁺, (Xu et al., 2013) making it an ideal exogenous Fe²⁺ to induce ferroptosis. For example, sequential release of the NPs based on the presence of heparinase was reported; these NPs were modified with β-cyclodextrin and coloaded with DOX, Fc, and TGF-β receptor inhibitor SB431542 (Figure 9) (Zhang et al., 2021). DOX and Fc could increase the intracellular ROS levels to activate ferroptosis and apoptosis and reduce MMP-9 expression to enhance FBT in the tumor. SB431542 could be gradually released due to the heparanase-driven nature, which prevented the tumor metastasis via modulating the TME, decreasing tumor-associated fibroblast activation, and reducing TGF-β secretion. Furthermore, ferroptosis-induced antitumor immune response enhanced the tumor therapy. A CDT nanomaterial, RSL3@COF–Fc, was fabricated by the covalent organic framework (COF), Fc, and RSL3 (Zhou et al., 2021). The RSL3@COF–Fc could promote the production of •OH in cancer cells, and the repair mechanism under oxidative stress was attenuated by the irreversible inhibition of the GPX4. Finally, these two ways synergistically resulted in massive LPO accumulation.

A multifunctional carbon monoxide (CO)/thermo/chemotherapy nanoplatform comprises the mesoporous carbon NPs (MCNPs) as NIR-responsive drug carriers and DOX and hydrophobic iron carbonyl (FeCO) as thermosensitive CO prodrug (Yao et al., 2019). The nanoplatform produced sufficient heat upon NIR illumination to trigger the release of CO and DOX in the acidic TME. The CO successfully increased the sensitivity of the cancer cells to chemotherapeutics through the ferroptosis pathway. Subsequently, the FeCO-DOX@MCNP nanoplatform showed high therapeutic efficacy in combination with chemotherapy, PTT, and gas therapy both in vitro and in vivo.

Ferritin is an iron-sequestering protein that plays key roles in iron delivery, cell proliferation, and immunosuppression (Shi et al., 2021). The novel protein-based nanomaterial BCFe@sorafenib was developed by covalently crosslinking the Ce6-conjugated bovine serum albumin (BSA) and ferritin, together with the sorafenib encapsulated inside the protein shell (Wang et al., 2021). Under hypoxic condition, the BCFe@sorafenib could be degraded to release more Ce6 after light irradiation, whereas the ferritin released Fe³⁺ to consume GSH to produce more ROS. In addition, the released sorafenib destroyed the tumor’s antioxidative defense to enhance oxidative damage. In addition, a novel carrier-free nanodrug NFER containing ferritin, erastin, and rapamycin was prepared by using an emulsification technique (Li et al., 2019). The NFER displayed strong ferroptosis capability by downregulating the GPX4 and increasing LPO production, which was increased by the presence of rapamycin. Using this nanodrug, tumor recurrence of the 4T1 tumor resection model was controlled.

The photic UC is achieved by the UCNPs that contain lanthanide or actinide metals. The Fe³⁺-containing UCNP and DOX were capsulated into the oxidized starch-based gel NPs (Figure 10) (Bao et al., 2019). As the core, the UCNPs that convert NIR light to ultraviolet (UV) light overcome the obstacle of limited penetration depth and reduced Fe³⁺ to Fe²⁺, which led to the deconstruction of gel networks of this nanomaterial and subsequently rapid release of Fe²⁺ and DOX. As a result, this nanomaterial could provide a safe and efficient platform for ferroptosis-/apoptosis-based anticancer therapy.

A versatile porphyrin-based manganese MOF (Mn-MOF) nanoplatform exhibited high catalase activity for the conversion of H₂O₂ to O₂, thus decreasing the intracellular GSH content and GPX4 activity and inhibiting the tumor growth and metastasis via inducing SDT and FBT (Figure 11) (Xu, Q. et al., 2021). In addition, the Mn-MOF efficiently reshaped the tumor immune microenvironment upon US treatment by increasing the activated CD8⁺ T cells and matured dendritic cells (DCs) and decreasing the myeloid-derived suppressor cells in tumor tissue. The arginine-rich manganese silicate nanobubbles (AMSNs) could be synthesized through a one-pot method with highly efficient GSH depletion (Wang et al., 2018). The arginine component provides ideal dispersibility, biocompatibility, and tumor-targeting capacity. Compared with the traditional NPs, the arginine-based ultrathin surface coating and nanobubble structure significantly improved the ability of the AMSNs to consume GSH, which led to GPX4 inactivation. In addition, the degradation of AMSNs led to the corelease of Mn²⁺ and DOX, which resulted in T1-weighted MRI and on-demand chemotherapeutic drug release for the synergistic cancer therapy. In addition, manganese-doped MSNPs (MMSNPs) possess the manganese–oxygen bonds that could consume GSH rapidly (Tang et al., 2019). MMSNPs were modified with FA-PFG and loaded with dihydroartemisinin (DHA) to form an innovative nanomaterial (Fei et al., 2020b). After endocytosis, the degradation of nanomaterials consumed intracellular GSH due to the reaction between the manganese–oxygen bonds and GSH, which resulted in the release of DHA and Mn²⁺. The sorafenib could also be loaded into MMSNPs to induce ferroptosis of tumor cells (Tang et al., 2019; Tang et al., 2020).

The MnO₂@HMCu_2−xS nanocomposites (HMCMs) for tumor ablation were reported (An et al., 2019). The HMCMs had the ability of depletion of GSH enhanced by PTT, thus inducing PTT-enhanced ferroptosis of cells by GPX4 inactivation. The GSH-responsive Mn²⁺ release increased the ROS concentration by a Fenton-like reaction, thus resulting in the accumulation of LPO. The rapamycin was encapsulated into the HMCM to improve sensitization of the tumor cells to ferroptosis. The HMCM showed an outstanding anticancer effect in vitro and in vivo. In addition, MnO_x nanospikes and ICD drugs were developed as cancer nanovaccines (Figure 12) (Ding et al., 2020). Because of the double induction of CDT mediated by Mn²⁺ and FBT that depleted GSH, MnO_x nanospikes could be used as an immune adjuvant for efficient antigen loading and ICD drugs. The nanovaccines achieved the TME-responsive, dual-mode MRI/PAI, while effectively inhibiting tumor growth and metastasis.

The salinomycin that conjugated with the Au NPs was used to kill breast cancer stem cells that were derived from CD24^low/CD44^high subpopulation (Zhao et al., 2019). The salinomycin-AuNPs exhibited higher ability to induce ferroptosis via higher iron accumulation and GPX4 inactivation. Pt-decorated Au nanostars were presented as novel nanoprodrugs for FBT against MDR tumors (Del Valle et al., 2020). Upon NIR light irradiation, Pt and Au were released, which resulted in GSH depletion, GPX4 inactivation, and accumulation of lipid hydroperoxides. The NIR light-activation of the prodrugs showed efficacy of FBT against tumors without long-term side effects in vivo.

The Ce6 and erastin could be self-assembled to form a novel nanodrug via hydrogen bonding and π–π interactions (Zhu et al., 2019). The erastin could induce accumulation of LPO via the Fenton reaction. Under the light irradiation, the generation of O₂ ensured efficient photochemical reactions to produce ROS. The imidazole ligand containing disulfide and Zn²⁺ was coordinated to form an MOF nanocarrier for Ce6 loading. Regardless of the light irradiation, nanocarriers loaded with Ce6 induced GSH depletion through the disulfide−thiol exchange reaction in 4T1 tumor cells (Meng et al., 2019). In the 4T1 tumor–bearing mouse model, the nanomaterials showed excellent in vivo tumor growth inhibition, and the animal survival rate was improved. However, the combined use of iron chelating agents weakened the antitumor ability of the nanocarrier because it restrained ferroptosis.

The nanoactivator was assembled by DOX, TA, and IR820. The endogenous iron stored in the endo-lysosome was fully utilized. In addition, the ferroptosis and its related oxidative stress were induced by an artificial intracellular positive feedback loop (Figure 13) (Xiong et al., 2021). Interestingly, this process could also promote the ICD-related immunotherapy through the endoplasmic reticulum stress. After the laser treatment, the intracellular ROS in cells could be effectively distributed in the lysosomes and endoplasmic reticulum to promote FBT and immunotherapy, respectively.

RSL3 can be loaded onto the non-iron nanomaterials. The ionizable block copolymer and phenylboronate ester (PBE) were integrated by covalent bonds to prepare a platform for RSL-3 delivery (Figure 14) (Song et al., 2021). At neutral pH, the NPs could stably embed RSL-3 in the hydrophobic core through π–π interaction with the PBE groups and release the payload in the endogenous vesicles through acidity-triggered cleavage of dynamic covalent bonds of PBE. In addition, the NPs could perform acid-activatable PDT by ionizing nuclear protonation and significantly recruiting tumor infiltrating T lymphocytes to secrete IFN-γ, and thus make the B16–F10 melanoma tumor sensitive to RSL-3–induced ferroptosis. The maltose ligand and azobenzene were linked by PEG and self-assembled to load RSL3, yielding Malt-PEG-Abz@RSL3 (Li et al., 2022). Malt-PEG-Abz@RSL3 micelles could actively target HepG2 because of the high expression of glucose transporters, thus achieving RSL3 delivery. Malt-PEG degraded to release RSL3 for inhibiting GPX4 activity, whereas NADPH that took part in synthesis of GSH and thioredoxin-SH2 [Trx (SH) 2] was consumed by the azobenzene moiety, resulting in the reduction of GSH and Trx (SH) 2. The azobenzene was also connected to a nitroimidazole-conjugated polypeptide and self-assembled with RSL3 (Guo, X. et al., 2020). Under anoxic conditions, the azobenzene moiety caused PEG to be removed and reinforced micelle uptake in 4T1 cells, while the nitroimidazole moiety not only resulted in the rapid release of RSL3 but also exhausted intracellular NADPH with the help of overexpression of nitroreductase in the tumor site.

The core-shell UCNPs (NaGdF4:20%Yb, 0.5%Tm³⁺@NaGdF4) could absorb NIR light and emit UV to transfer azobenzene combretastatin A4 (azobenzene-CA4) to activate azobenzene-CA4, while UV light could induce reduction of intracellular Fe³⁺ to Fe²⁺ (Figure 15) (Zhu et al., 2020). Upon NIR irradiation, the viability of the triple-negative breast cancer cells treated with nanocarriers loaded with azobenzene-CA4 evidently decreased. Another UCNP (NaYF4:20%Yb, 2%Er@NaYF4) was coated by the MS and liposome to encapsulate Ce6 and buthionine sulfoximine (BSO) (Li D et al., 2021; Li Z et al., 2021). Notably, Ce6-induced ROS production, BSO-caused GSH depletion, and inactivation of GPX4 could amplify apoptosis and ferroptosis. Efficient tumor destruction led to increased exposure of high mobility group box 1 (HMGB1) and calreticulin enhancing antitumor immune responses, including maturation of DCs and effector function of tumor-infiltrating T lymphocytes, which resulted in the elimination of the residual melanoma cells.