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 µ m in the saline group) disrupts membrane rigidity, augmenting intratumoral drug retention to 87% (vs 39% with free DOX); 2) ZCM converts COD‐generated H 2 O 2 into cytotoxic hydroxyl radicals (·OH), realizing pathological cholesterol‐to‐ reactive oxygen species (ROS) reprogramming for selective tumor oxidation; 3) Zn 2+ 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.