A cholesterol-depleting dual-functional platform synergistically amplifying ferroptosis and immunogenic cell death for osteosarcoma therapy.

Abstract

The high metastatic potential and chemotherapy resistance of osteosarcoma severely limit clinical efficacy, necessitating the development of novel therapeutic strategies. This study addresses the core bottlenecks of compensatory GPX4 upregulation and insufficient immunogenicity in ferroptosis therapy by constructing a dual-functional nanotherapeutic platform (Zn/FeC@MβCD) that synergizes cholesterol depletion and ferroptosis. The platform was fabricated by doping zinc ions (Zn2⁺) into MIL-100(Fe)-derived porous carbon (FeC-MOF), followed by coating with methyl-β-cyclodextrin (MβCD). In vitro studies demonstrated that MβCD efficiently depletes tumor cell membrane cholesterol, disrupts lipid raft stability, and downregulates GPX4 expression, consistent with transcriptional suppression, thereby sensitizing cells. Concurrently, the Zn/FeC core not only exhibits robust peroxidase-like and glutathione oxidase-like activities, catalyzing reactive oxygen species burst and glutathione consumption, but the released Zn2⁺ also is reported to directly inhibit GPX4 enzymatic activity, and our data show that Zn doping further enhances GPX4 suppression and lipid peroxidation. This dual mechanism of "metabolic intervention" and "catalytic attack" synergistically deeply inhibits GPX4 function, triggering intense lipid peroxidation and thereby efficiently inducing ferroptosis. Importantly, this process is accompanied by significant calreticulin exposure, and the release of ATP and HMGB1, initiating robust immunogenic cell death (ICD). In vivo antitumor experiments confirmed that Zn/FeC@MβCD significantly inhibits osteosarcoma growth, effectively promotes dendritic cell maturation, increases cytotoxic T cell tumor infiltration, and upregulates a pro-inflammatory cytokine profile, successfully reversing the "cold" tumor microenvironment to a "hot" state. This study provides a new paradigm for activating antitumor immunity by synergistically regulating cell metabolism and death modes, offering a promising nanotherapeutic strategy to overcome GPX4-mediated ferroptosis resistance, with potential for future evaluation in metastatic models.

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