A Mitochondria‐Targeted Biomimetic Nanocarrier Improves Oxygen Metabolism and Potentiates Chemo‐Sonodynamic Antitumor Therapy

Abstract Sonodynamic therapy (SDT) exhibits high tissue penetration and negligible radiation damage to normal tissue, but it hampered by the limited oxygen in tumor, which can be potentiated via improving oxygen metabolism and increasing oxygen utilization efficiency. Herein, a multifunctional biomimetic nanocarrier (VI@R‐T) is fabricated by encapsulating vanadium‐based nanozyme (VO _x ) with dual enzyme activity and sonosensitizer indocyanine green (ICG) into the mitochondria‐targeted erythrocyte vesicle. The nanocarrier can be targeted to the mitochondria, where the enzyme in red blood cell membrane catalyzed endogenous H ₂ O ₂ to increase O ₂ content for alleviating hypoxia. Meanwhile, nanozyme exhibits the NADH oxidase (NOX) activity affecting the nicotinamide adenine dinucleotide/flavin adenine dinucleotide (NADH/FAD) balance in the cellular oxidative phosphorylation, which impairs the mitochondrial electron transport chain and reduces intracellular oxygen consumption, thereby significantly improving tumor oxygen metabolism and the efficacy of SDT. In addition, nanozyme also shows peroxide‐like activity in tumor microenvironment (TME), and generates highly toxichydroxyl radical (OH) for ROS‐amplifying oxidative stress. Deep‐hypothermia potentiated 2D/3D autofluorescence imaging also monitored the nanocarrier effectively disrupt the balance of NADH/FAD in the tumor. This work provides anew approach for designing ROS‐based biomimetic nanomedical platform for tumor hypoxia relief.