Robust Dual Enzyme Cascade-Catalytic Cholesterol Depletion for Reverse Tumor Multidrug Resistance

Although combination drugs and P-glycoprotein inhibitors are the main methods to solve multidrug resistance, these methods ignore the pathological structure of drug-resistant cells and extremely limit curative effect. Herein, a new paradigm of reversing multidrug resistance with abnormal expression of cholesterol as the target is proposed, which uses the cascade catalysis of "natural enzyme" cholesterol oxidase (COD) and "nanoenzyme" Cu²⁺ -modified zirconium-based metal-organic framework (ZrMOF(Cu)) to convert cholesterol into the highly cytotoxic hydroxyl radicals. The doxorubicin (DOX)-loaded nanoparticles (DOX@COD-MOF) can significantly reduce the cholesterol content of cancer cells via COD, which decrease the rigidity of drug resistant cancer cell membranes and restore the sensitivity of multidrug-resistant cells to DOX. Afterward, DOX@COD-MOF is encapsulated by cancer cell membranes (CCM) to construct a bionic "dual enzyme catalytic cascade nanoreactor" (DOX@COD-MOF@CCM). Such a rational design presents a preferential accumulation tendency to tumor sites due to the homologous targeting mechanism of CCM, and affords 94.4% in tumor growth suppression without systemic toxicity in vivo. This work aims to achieve the therapeutic purpose of high efficiency and low toxicity. It has the characteristics of "converting enemy into friend, " and opens up a promising way for effectively reversing multidrug resistance of tumors.