Innovative DCZCMC Platform: Dual Regulation of Cholesterol Dynamics and the cGAS/STING Pathway Activation to Combat Drug Resistance in Tumor Therapy.

Chemoresistance remains a daunting challenge in bladder cancer therapy, primarily driven by cholesterol-enriched rigid membranes that impede drug penetration and an immunosuppressive tumor microenvironment (TME) that evades immune surveillance. Herein, a biomimetic nanoplatform (DOX@COD-ZCM@CS, DCZCMC) is reported engineered to orchestrate metabolic-immunological crosstalk for synergistic reversal of chemoresistance. This integrated system comprises a Zn-Co metal-organic framework (Zn-Co-MOF, ZCM) core loaded with cholesterol oxidase (COD) and doxorubicin (DOX), surface-functionalized with chondroitin sulfate (CS) for tumor-specific targeting. Mechanistically, DCZCMC achieves three-tiered synergism: 1) COD-mediated cholesterol depletion (71.5% reduction, 111.2 vs 389.8 µm in the saline group) disrupts membrane rigidity, augmenting intratumoral drug retention to 87% (vs 39% with free DOX); 2) ZCM converts COD-generated H2O2 into cytotoxic hydroxyl radicals (·OH), realizing pathological cholesterol-to- reactive oxygen species (ROS) reprogramming for selective tumor oxidation; 3) Zn2+ release triggers mitochondrial DNA (mtDNA) leakage, activating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway to amplify interferon-β (IFN-β) and High Mobility Group Protein 1 (HMGB1) secretion, thereby driving dendritic cells (DCs) maturation and adaptive immune activation. In drug-resistant xenografts, DCZCMC exhibits exceptional antitumor efficacy (95.6% tumor suppression) without systemic toxicity. This self-amplifying "metabolic priming-immune activation" cascade represents a paradigm shift in overcoming chemoresistance, offering a transformative strategy for bladder cancer and other malignancies characterized by metabolic-immunological dysregulation.