Acidic/hypoxia dual-alleviated nanoregulators for enhanced treatment of tumor chemo-immunotherapy.

Chemotherapy plays a crucial role in triple-negative breast cancer (TNBC) treatment as it not only directly kills cancer cells but also induces immunogenic cell death. However, the chemotherapeutic efficacy was strongly restricted by the acidic and hypoxic tumor environment. Herein, we have successfully formulated PLGA-based nanoparticles concurrently loaded with doxorubicin (DOX), hemoglobin (Hb) and CaCO3 by a CaCO3-assisted emulsion method, aiming at the effective treatment of TNBC. We found that the obtained nanomedicine (DHCaNPs) exhibited effective drug encapsulation and pH-responsive drug release behavior. Moreover, DHCaNPs demonstrated robust capabilities in neutralizing protons and oxygen transport. Consequently, DHCaNPs could not only serve as oxygen nanoshuttles to attenuate tumor hypoxia but also neutralize the acidic tumor microenvironment (TME) by depleting lactic acid, thereby effectively overcoming the resistance to chemotherapy. Furthermore, DHCaNPs demonstrated a notable ability to enhance antitumor immune responses by increasing the frequency of tumor-infiltrating effector lymphocytes and reducing the frequency of various immune-suppressive cells, therefore exhibiting a superior efficacy in suppressing tumor growth and metastasis when combined with anti-PD-L1 (αPD-L1) immunotherapy. In summary, this study highlights that DHCaNPs could effectively attenuate the acidic and hypoxic TME, offering a promising strategy to figure out an enhanced chemo-immunotherapy to benefit TNBC patients.

Multiple Immunomodulatory Strategies Based on Targeted Regulation of Proprotein Convertase Subtilisin/Kexin Type 9 and Immune Homeostasis against Hepatocellular Carcinoma.

Immunotherapy is the most promising systemic therapy for hepatocellular carcinoma. However, the outcome remains poor. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a role in altering cell-surface protein levels, potentially undermining the efficacy of immunotherapy against tumors. This highlights its potential as a target for antitumor therapy. Herein, CaCO3-based nanoparticles coencapsulated with DOX, an immunogenic cell death (ICD) inducer, and evolocumab was developed to enhanced the efficacy of immunotherapy. The obtained DOX/evolocumab-loaded CaCO3 nanoparticle (named DECP) exhibits a good capacity of acid neutralization and causes ICD of cancer cells. In addition, DECP is able to evaluate the cell-surface level of MHC-I, a biomarker that correlates positively with patients' overall survival. Upon intravenous injection, DECP accumulates within the tumor site, leading to growth inhibition of hepa1-6 bearing subcutaneous tumors. Specifically, DECP treatment causes augmented ratios of matured dendritic cells, tumor-infiltrating CD8+ T cells and natural killing cells, while concurrently depleting Foxp3+ regulatory T cells. Peritumoral delivery of DECP enhances the immune response of distant tumors and exhibits antitumor effects when combined with intravenous αPD-L1 therapy in a bilateral tumor model. This study presents CaCO3-based nanoparticles with multiple immunomodulatory strategies against hepatocellular carcinoma by targeting PCSK9 inhibition and modulating immune homeostasis in the unfavorable TME.

Mesenchymal stem cell-derived extracellular vesicles in skin wound healing: roles, opportunities and challenges.

Skin wounds are characterized by injury to the skin due to trauma, tearing, cuts, or contusions. As such injuries are common to all human groups, they may at times represent a serious socioeconomic burden. Currently, increasing numbers of studies have focused on the role of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) in skin wound repair. As a cell-free therapy, MSC-derived EVs have shown significant application potential in the field of wound repair as a more stable and safer option than conventional cell therapy. Treatment based on MSC-derived EVs can significantly promote the repair of damaged substructures, including the regeneration of vessels, nerves, and hair follicles. In addition, MSC-derived EVs can inhibit scar formation by affecting angiogenesis-related and antifibrotic pathways in promoting macrophage polarization, wound angiogenesis, cell proliferation, and cell migration, and by inhibiting excessive extracellular matrix production. Additionally, these structures can serve as a scaffold for components used in wound repair, and they can be developed into bioengineered EVs to support trauma repair. Through the formulation of standardized culture, isolation, purification, and drug delivery strategies, exploration of the detailed mechanism of EVs will allow them to be used as clinical treatments for wound repair. In conclusion, MSC-derived EVs-based therapies have important application prospects in wound repair. Here we provide a comprehensive overview of their current status, application potential, and associated drawbacks.

Biomaterials evolution: from inert to instructive.

The field of biomaterials has experienced substantial evolution in recent years, driven by advancements in materials science and engineering. This has led to an expansion of the biomaterials definition to include biocompatibility, bioactivity, bioderived materials, and biological tissues. Consequently, the intended performance of biomaterials has shifted from a passive role wherein a biomaterial is merely accepted by the body to an active role wherein a biomaterial instructs its biological environment. In the future, the integration of bioinspired designs and dynamic behavior into fabrication technologies will revolutionize the field of biomaterials. This perspective presents the recent advances in the evolution of biomaterials in fabrication technologies and provides a brief insight into smart biomaterials.

The role of metabolic reprogramming of oxygen-induced macrophages in the dynamic changes of atherosclerotic plaques.

Atherosclerosis (As) is a chronic vascular inflammatory disease. Macrophages are the most important immune cells in atherosclerotic plaques, and the phenotype of plaque macrophages shifts dynamically to adapt to changes in the plaque microenvironment. The aerobic microenvironment of early atherosclerotic plaques promotes the transformation of M2/alternatively activated macrophages mainly through oxidative phosphorylation; the anoxic microenvironment of advanced atherosclerotic plaques mainly promotes the formation of M1/classically activated macrophages through anaerobic glycolysis; and the adventitia angiogenesis of aged atherosclerotic plaques leads to an increase in the proportion of M2/M1 macrophages. Therefore, this review deeply elucidates the dynamic change mechanism of plaque macrophages and the regulation of plaque oxygen content and immune metabolism to find new targets for the treatment of As.

Monodisperse CaCO3-loaded gelatin microspheres for reversing lactic acid-induced chemotherapy resistance during TACE treatment.

Transarterial chemoembolization (TACE) is an important approach for the treatment of unresectable hepatocellular carcinoma (HCC). However, the lactic acid-induced acidic tumor microenvironment (TME) may reduce the therapeutic outcome of TACE. Herein, monodispersed gelatin microspheres loaded with calcium carbonate nanoparticles (CaNPs@Gel-MS) as novel embolic agents were prepared by a simplified microfluidic device. It was found that the particle size and homogeneity of as-prepared CaNPs@Gel-MS were strongly dependent on the flow rates of continuous and dispersed phases, and the inner diameter of syringe needle. The introduction of CaNPs provided the gelatin microspheres with an enhanced ability to encapsulate the chemotherapeutic drug of DOX, as well as a pH-responsive sustained drug release behavior. In vitro results revealed that CaNPs@Gel-MS could largely increase the cellular uptake and chemotoxicity of DOX by neutralizing the lactic acid in the culture medium. In addition, CaNPs@Gel-MS exhibited an excellent and persistent embolic efficiency in a rabbit renal model. Finally, we found that TACE treatment with DOX-loaded CaNPs@Gel-MS (DOX/CaNPs@Gel-MS) had a much stronger ability to inhibit tumor growth than the DOX-loaded gelatin microspheres without CaNPs (DOX@Gel-MS). Overall, CaNPs@Gel-MS could be a promising embolic microsphere that can significantly improve anti-HCC ability by reversing lactic acid-induced chemotherapy resistance during TACE treatment.

Inactivation of KDM5A suppresses growth and enhances chemosensitivity in liver cancer by modulating ROCK1/PTEN/AKT pathway.

Liver cancer is a kind of malignant tumor with poor sensitivity to chemotherapy. It is urgent to investigate approaches to improve the outcome of chemotherapy. KDM5A has been reported to be an oncogene in various cancers and is associated with drug resistance. However, the functions of KDM5A in chemotherapeutic sensitivity of liver cancer not been well illustrated. In this study, we found that KDM5A was upregulated in liver cancer tissue and cell lines. KDM5A knockdown using a gene interference strategy suppressed the growth of liver cancer in vitro and in vivo. CPI-455, a pharmacological inactivation of KDM5A enhanced the cytotoxicity of cisplatin (CDDP) in liver cells. CPI-455 and CDDP cotreatment resulted in apoptosis and mitochondrial dysfunction. We also found that knockdown or inactivation of KDM5A resulted in the downregulation of ROCK1, an oncogene regulating the activation of the PTEN/AKT signaling pathway. In particular, overexpression of ROCK1 or SF1670, a pharmacological inhibitor of PTEN, alleviated the cytotoxicity of CPI-455 and CDDP cotreatment. In HCCLM3 xenografts, CPI-455 and CDDP cotreatment dramatically inhibited the growth of xenograft tumor compared to CPI-455 or CDDP treatment alone. In conclusion, this study suggested that targeting the inactivation of KDM5A is an efficient strategy to enhance the chemosensitivity of liver cancer cells to CDDP by modulating the ROCK1/PTEN/AKT signaling pathway.

SMYD3 associates with the NuRD (MTA1/2) complex to regulate transcription and promote proliferation and invasiveness in hepatocellular carcinoma cells.

BACKGROUND: SMYD3, a member of the SET and MYND domain-containing (SMYD) family, is a histone methyltransferase (HMT) and transcription factor that plays an important role in transcriptional regulation in human carcinogenesis. RESULTS: Using affinity purification and mass spectrometry assays to identify SMYD3-associated proteins in hepatocellular carcinoma (HCC) cells, we found several previously undiscovered SMYD3-interacting proteins, including the NuRD (MTA1/2) complex, the METTL family, and the CRL4B complex. Transcriptomic analysis of the consequences of knocking down SMYD3, MTA1, or MTA2 in HCC cells showed that SMYD3/NuRD complex targets a cohort of genes, some of which are critically involved in cell growth and migration. qChIP analyses showed that SMYD3 knockdown led to a significant reduction in the binding of MTA1 or MTA2 to the promoters of IGFBP4 and led to a significant decrease in H4K20me3 and a marked increase in H4Ac at the IGFBP4 promoter. In addition, we demonstrated that SMYD3 promotes cell proliferation, invasion, and tumorigenesis in vivo and in vitro and found that its expression is markedly upregulated in human liver cancer. Knockdown of MTA1 or MTA2 had the same effect as knockdown of SMYD3 on proliferation and invasion of hepatocellular carcinoma cells. Catalytic mutant SMYD3 could not rescue the phenotypic effects caused by knockdown of SMYD3. Inhibitors of SMYD3 effectively inhibited the proliferation and invasiveness of HCC cells. CONCLUSIONS: These findings revealed that SMYD3 could transcriptionally repress a cohort of target genes expression by associating with the NuRD (MTA1/2) complex, thereby promoting the proliferation and invasiveness of HCC cells. Our results support the case for pursuing SMYD3 as a practical prognostic marker or therapeutic target against HCC.

Integrated application of transcriptome and metabolomics reveals potential therapeutic targets for the polarization of atherosclerotic macrophages.

The polarization of macrophages often leads to severe calcification and necrosis in aged atherosclerotic plaques, which eventually leads to poor prognosis of ischaemic cardiovascular and cerebrovascular diseases. More reliable diagnostic methods are urgently needed to discover therapeutic targets of macrophage polarization in aged atherosclerotic plaques. Metabolomics of aged plaques (n = 20) and macrophage polarization transcriptomes (n = 30) were integrated to identify metabolic therapeutic targets of macrophage polarization associated with aged plaque. Finally, metabolic inhibitors were used to verify the reliability of the target genes. Integrated multiomics analysis revealed that 6 metabolic pathways (including 21 genes) regulate macrophage polarization in aged atherosclerosis. Targeted treatment of macrophage polarization with metabolic inhibitors can effectively reduce the adverse risk of aged atherosclerosis. The combination of transcriptomics and metabolomics approaches can identify effective therapeutic targets for macrophage polarization in arteriosclerosis.

ICAM-1 targeted thermal-sensitive micelles loaded with tofacitinib for enhanced treatment of rheumatoid arthritis via microwave assistance.

Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease without effective treatment. Tofacitinib (TOF) is a JAK inhibitor that can be used for RA therapy, but it still faces the problems of nonspecific distribution and relatively low therapeutic effect. Herein, ICAM-1-modified TOF-loaded P(AN-co-AAm)-PEG micelles (AI-TM) were developed, which can result in an enhanced RA therapy when combining with microwave hyperthermia (MH). It was found that AI-TM could rapidly release the encapsulated TOF under a thermal condition of >43 °C, which was due to the fact that the polymeric micelles has an upper critical solution temperature (UCST) of 43 °C. AI-TM could specifically distribute into the inflamed joints of RA mice, which is associated with the high affinity between anti-ICAM-1 and overexpressed ICAM-1 receptors. Moreover, the combination of AI-TM and MH could result in a remarkably enhanced anti-rheumatic activity, which was related to the RA-targeted ability of AI-TM, the rapid TOF release under MH, and the combined effect between TOF and MH treatment. Our study definitely provides a novel strategy for effective treatment of RA.

xCT contributes to colorectal cancer tumorigenesis through upregulation of the MELK oncogene and activation of the AKT/mTOR cascade.

Colorectal cancer (CRC) is one of the most commonly diagnosed and deadly malignant tumors globally, and its occurrence and progression are closely related to the poor histological features and complex molecular characteristics among patients. It is urgent to identify specific biomarkers for effective treatment of CRC. In this study, we performed comprehensive experiments to validate the role of xCT expression in CRC tumorigenesis and stemness and confirmed xCT knockdown significantly suppressed the proliferation, migration, and stemness of CRC cells in vitro and effectively inhibited CRC tumorigenesis and metastasis in vivo. In addition, bioinformatic analysis and luciferase assays were used to identify E2F1 as a critical upstream transcription factor of SLC7A11 (the gene encoding for xCT) that facilitated CRC progression and cell stemness. Subsequent RNA sequencing, western blotting, rescue assay, and immunofluorescence assays revealed MELK directly co-expressed with xCT in CRC cells, and its upregulation significantly attenuated E2F1/xCT-mediated tumorigenesis and stemness in CRC. Further molecular mechanism exploration confirmed that xCT knockdown may exert an antitumor effect by controlling the activation of MELK-mediated Akt/mTOR signaling. Erastin, a specific inhibitor of xCT, was also proven to effectively inhibit CRC tumorigenesis and cell stemness. Altogether, our study showed that E2F1/xCT is a promising therapeutic target of CRC that promotes tumorigenesis and cell stemness. Erastin is also an effective antitumoral agent for CRC.

Homogenous multifunctional microspheres induce ferroptosis to promote the anti-hepatocarcinoma effect of chemoembolization.

Transcatheter arterial chemoembolization (TACE) is one of the main palliative therapies for advanced hepatocellular carcinoma (HCC), which is also regarded as a promising therapeutic strategy for cancer treatment. However, drug-loaded microspheres (DLMs), as commonly used clinical chemoembolization drugs, still have the problems of uneven particle size and unstable therapeutic efficacy. Herein, gelatin was used as the wall material of the microspheres, and homogenous gelatin microspheres co-loaded with adriamycin and Fe3O4 nanoparticles (ADM/Fe3O4-MS) were further prepared by a high-voltage electrospray technology. The introduction of Fe3O4 nanoparticles into DLMs not only provided excellent T2-weighted magnetic resonance imaging (MRI) properties, but also improved the anti-tumor effectiveness under microwave-induced hyperthermia. The results showed that ADM/Fe3O4-MS plus microwave irradiation had significantly better antitumor efficacy than the other types of microspheres at both cell and animal levels. Our study further confirmed that ferroptosis was involved in the anti-tumor process of ADM/Fe3O4-MS plus microwave irradiation, and ferroptosis marker GPX4 was significantly decreased and ACSL4 was significantly increased, and ferroptosis inhibitors could reverse the tumor cell killing effect caused by ADM/Fe3O4-MS to a certain extent. Our results confirmed that microwave mediated hyperthermia could amplify the antitumor efficacy of ADM/Fe3O4-MS by activating ferroptosis and the introduction of Fe3O4 nanoparticles can significantly improve TACE for HCC. This study confirmed that it was feasible to use uniform-sized gelatin microspheres co-loaded with Fe3O4 nanoparticles and adriamycin to enhance the efficacy of TACE for HCC.

DNA-Functionalized Liposomes In Vivo Fusion for NIR-II/MRI Guided Pretargeted Ferroptosis Therapy of Metastatic Breast Cancer.

In clinic, metastasis is still the main reason for death for cancer patients. Therefore, it is necessary to track cancer metastases accurately, kill cancer cells effectively, and then improve the prognosis of patients with advanced cancer. Therefore, we designed a liposome-based pretargeted system modified with single-stranded DNA and targeting peptide injected in sequence and then assembled in vivo for multimodality imaging-guided pretargeted synergistic therapy of metastatic breast cancer. The pretargeted system is composed of the first liposome, loaded with near-infrared fluorescence imaging (NIR-II) probe downconversion nanoprobes (DCNP) and magnetic resonance imaging (MRI) contrast agent SPIO (L1/C-Lipo/DS), for primary/metastatic tumor MRI/NIR-II dual-modal imaging, and the second liposome, loaded with glucose oxidase (GOx) and doxorubicin (DOX) (L2/C-Lipo/GD), as the therapeutic component. The SPIO in L1/C-Lipo/DS accumulated in the tumor tissue will provide a necessary iron ion for the therapeutic liposome (L2/C-Lipo/GD) to exert the pretargeted ferroptosis therapy to cancer cells. We demonstrate that the DNA-mediated pretargeting strategy can realize the multimodality imaging-guided synergistically enhanced antitumor effect between the two liposomes. This pretargeted and synergistic in vivo assembly nanomedicine strategy for diagnosis and treatment holds clinical translation potential for cancer management.

HIF-2α-targeted interventional chemoembolization multifunctional microspheres for effective elimination of hepatocellular carcinoma.

Transcatheter arterial chemoembolization (TACE) is widely used for the treatment of advanced hepatocellular carcinoma (HCC). However, the long-term hypoxic microenvironment caused by TACE seriously affects the therapeutic effect of TACE. HIF-2α plays a crucial role on the chronic hypoxia process, which might be an ideal target for TACE therapy. Herein, a multifunctional polyvinyl alcohol (PVA)/hyaluronic acid (HA)-based microsphere (PT/DOX-MS) co-loaded with doxorubicin (DOX) and PT-2385, an effective HIF-2α inhibitor, was developed for enhanced TACE treatment efficacy. In vitro and in vivo studies revealed that PT/DOX-MS had a superior ability to treat HCC by blocking the tumor cells in G2/M phase, prompting cell apoptosis, and inhibiting tumor angiogenesis. The antitumor mechanisms of PT/DOX-MS were possibly due to that the introduction of PT-2385 could effectively inhibit the expression level of HIF-2α in hypoxic HCC cells, thereby down-regulating the expression levels of Cyclin D1, VEGF and TGF-α. In addition, the combination of DOX and PT-2385 could jointly inhibit VEGF expression, which was another reason accounting for the combined anti-cancer effect of PT/DOX-MS. Overall, our study demonstrated that PT/DOX-MS is a promising embolic agent for enhanced HCC treatment via the combined effect of hypoxia microenvironment improvement, chemotherapy, and embolization.

Piperlongumine synergistically enhances the antitumour activity of sorafenib by mediating ROS-AMPK activation and targeting CPSF7 in liver cancer.

Sorafenib, a multikinase inhibitor, is the first-line agent for advanced liver cancer. Sorafenib strongly inhibits both cell proliferation and tumour angiogenesis. However, the development of drug resistance hampers its anticancer efficacy. To improve the antitumour activity of sorafenib, we demonstrate that piperlongumine (PL), an alkaloid isolated from the fruits and roots of Piper longum L., enhances the cytotoxicity of sorafenib in HCCLM3 and SMMC7721 cells using the cell counting kit-8 test. Flow cytometry analysis indicated that PL and sorafenib cotreatment induced robust reactive oxygen species (ROS) generation and mitochondrial dysfunction, thereby increasing the number of apoptotic cells and the ratio of G2/M phase cells in both HCCLM3 and SMMC7721 cells. Furthermore, AMP-protein kinase (AMPK) signalling was activated by excess ROS accumulation and mediated growth inhibition in response to PL and sorafenib cotreatment. RNA-sequencing analysis indicated that PL treatment disrupted RNA processing in HCCLM3 cells. In particular, PL treatment decreased the expression of cleavage and polyadenylation specificity factor 7 (CPSF7), a subunit of cleavage factor I, in a time- and concentration-dependent manner in HCCLM3 and SMMC7721 cells. CPSF7 knockdown using a gene interference strategy promoted growth inhibition of PL or sorafenib monotherapy, whereas CPSF7 overexpression alleviated the cytotoxicity of sorafenib in cultured liver cancer cells. Finally, PL and sorafenib coadministration significantly reduced the weight and volume of HCCLM3 cell xenografts in vivo. Taken together, our data indicate that PL displays potential synergistic antitumour activity in combination with sorafenib in liver cancer.

Fucoidan-based dual-targeting mesoporous polydopamine for enhanced MRI-guided chemo-photothermal therapy of HCC via P-selectin-mediated drug delivery.

The development of novel theranostic agents with outstanding diagnostic and therapeutic performances is still strongly desired in the treatment of hepatocellular carcinoma (HCC). Here, a fucoidan-modified mesoporous polydopamine nanoparticle dual-loaded with gadolinium iron and doxorubicin (FMPDA/Gd3+/DOX) was prepared as an effective theranostic agent for magnetic resonance imaging (MRI)-guided chemo-photothermal therapy of HCC. It was found that FMPDA/Gd3+/DOX had a high photothermal conversion efficiency of 33.4% and excellent T1-MRI performance with a longitudinal relaxivity (r1) value of 14.966 mM-1·s - 1. Moreover, the results suggested that FMPDA/Gd3+/DOX could effectively accumulate into the tumor foci by dual-targeting the tumor-infiltrated platelets and HCC cells, which resulted from the specific interaction between fucoidan and overexpressed p-selectin receptors. The excellent tumor-homing ability and MRI-guided chemo-photothermal therapy therefore endowed FMPDA/Gd3+/DOX with a strongest ability to inhibit tumor growth than the respective single treatment modality. Overall, our study demonstrated that FMPDA/Gd3+/DOX could be applied as a potential nanoplatform for safe and effective cancer theranostics.

Microwave hyperthermia-responsible flexible liposomal gel as a novel transdermal delivery of methotrexate for enhanced rheumatoid arthritis therapy.

Methotrexate (MTX) as an anti-inflammatory drug for the treatment of rheumatoid arthritis (RA) through oral and injectable administration is still problematic in the clinic. Herein, a MTX-loaded thermal-responsible flexible liposome (MTFL) incorporated within a carbomer-based gel was prepared as a novel transdermal agent (MTFL/Gel) for effective treatment of RA. It was found that MTFL had an average size of approximately 90 nm, which could rapidly release the drug under thermal conditions. The prepared MTFL/Gel could remarkably increase the MTX skin permeation as compared with free MTX, which was possibly due to the deformable membrane of flexible liposomes. Moreover, the results suggested MTFL/Gel could lead to a remarkably enhanced RA treatment when in combination with microwave hyperthermia. The superior ability of MTFL/Gel to alleviate RA response was attributed to the excellent skin permeation, thermal-responsible drug release, and synergistic anti-arthritic effect of MTX chemotherapy and microwave-induced hyperthermia therapy. Overall, the MTFL/Gel with dual deformable and thermal-responsible performances could be used as a novel promising transdermal agent for enhanced treatment of RA.

A Luminol-Based Self-Illuminating Nanocage as a Reactive Oxygen Species Amplifier to Enhance Deep Tumor Penetration and Synergistic Therapy.

The dense extracellular matrix (ECM) in tumor tissues resists drug diffusion into tumors and leads to a poor prognosis. To address this problem, glucose oxidase (GOx)-modified ferritin loaded with luminol-curcumin was fabricated. Once delivered to the tumor, this luminol-based self-illuminating nanocage could actively convert glucose to reactive oxygen species (ROS) to achieve starvation therapy. Then, excessive ROS were transmitted to luminol, thereby emitting 425 nm blue-violet light. Momentarily, light was further absorbed by curcumin and ROS production was amplified. Abundant ROS helps break down the ECM network to penetrate deep into tumors. In addition, ROS produced after cell internalization can induce apoptosis of tumor cells by decreasing the mitochondrial membrane potential and can promote ferroptosis by consuming reduced glutathione. Effective penetration and multiple pathways inducing tumor cell death contributed to the efficient antitumor effect (tumor inhibition rate of GOx-modified ferritin loaded with luminol-curcumin: 71.73%). This study developed a glucose-driven self-illuminating nanocage for active tumor penetration via ROS-mediated destruction of the ECM and provided the synergetic mechanism of apoptosis and ferroptosis.