Erythrocyte Membrane Camouflaged Metal–Organic Framework Nanodrugs for Remodeled Tumor Microenvironment and Enhanced Tumor Chemotherapy

Abstract The abundant extracellular matrix (ECM) in solid tumors causes limited drug penetration and hypoxia‐mediated chemoresistance, which lead to poor chemotherapy outcomes. To solve this problem, a biomimetic metal–organic framework nanodrug (ZIF‐8‐DOX‐LY‐RM) is developed with red blood cell membrane (RM) camouflage and encapsulation of type 1 transforming growth factor β receptor (TGFBR1) inhibitor and doxorubicin (DOX) for efficient chemotherapy. Based on the biomimetic properties of the erythrocyte membrane, ZIF‐8‐DOX‐LY‐RM can effectively accumulate in tumor tissues with immune escape and prolonged blood circulation. Then, the enriched nanodrug ZIF‐8‐DOX‐LY‐RM releases the TGFBR1 to remove collagen, subsequently leading to enhanced nanodrug penetration and increased oxygen supply. The abundant oxygen supply then relieves hypoxia‐mediated chemoresistance of DOX through increased cellular uptake and elevated reactive oxygen species production. The in vivo studies demonstrate the outstanding performance of ZIF‐8‐DOX‐LY‐RM nanoparticles in chemotherapy of cancer. This work presents an ECM normalization strategy for the synergistic collagen depletion and hypoxia alleviation and opens a promising avenue for effective chemotherapy of solid tumors.