Nanocatalytic Mitochondrial Oxidative Stress Amplification and Mitophagy Disruption for Efficient Tumor Catalytic Therapy

ABSTRACT Despite its attractive therapeutic potentials, nanocatalytic cancer therapy faces substantial challenges in delivery efficiency and target specificity. Organelle‐targeted approaches, particularly those focusing on mitochondria, offer enhanced therapeutic precision. In this study, we have developed a mitochondria‐targeted nanotherapeutic platform based on ultrasmall cobalt single‐atom nanocatalysts functionalized with triphenylphosphine (TPP) and co‐loaded with chloroquine (CQ) (Co‐SA‐TPP@CQ) for enhanced tumor catalytic therapy. Following precise mitochondrial localization, the nanocatalysts could catalyze the in situ generation of superoxide anions (•O 2 − ) and molecular oxygen (O 2 ). The produced oxidative stress disrupts mitochondrial electron transport chain (ETC) function, which serves as an endogenous electron donor to further reduce O 2 to •O 2 − , thereby establishing a self‐sustaining oxidative stress amplification cascade. Simultaneously, the released CQ effectively inhibits protective mitophagy, preventing the clearance of accumulating dysfunctional mitochondria. This dual‐functional mechanism combines the amplified oxidative damage with the blockade of mitophagy flux, ultimately triggering efficient tumor cell apoptosis. Our findings provide a robust paradigm in precision nanocatalytic medicine for harnessing intrinsic mitochondrial biochemistry while evading cellular defense mechanisms.