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

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 (•O₂ ^-) and molecular oxygen (O₂). The produced oxidative stress disrupts mitochondrial electron transport chain (ETC) function, which serves as an endogenous electron donor to further reduce O₂ to •O₂ ^-, 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.