CaO ₂ -Powered Nanomotors with Enhanced Cellular Uptake and Lysosomal Escape for Cuproptosis and Reactive Oxygen Species-Mediated Synergistic Cancer Therapy

Low cellular uptake and lysosomal degradation of nanomaterials in tumors pose a major challenge for reactive oxygen species (ROS)-involved chemodynamic therapy. Here, we report a self-propelled polyethylenimine-modified calcium peroxide@bovine serum albumin/copper/catalase-hesperidin (CaO 2 –PEI@BSA/Cu/CAT@HES, CP@BCC-HES) nanomotor capable of enhancing diffusion and cellular uptake. This nanomotor is engineered by incorporating Cu-based nanoparticles into functionalized CaO 2 nanoparticles, followed by Hesperidin loading for systematic tumor therapy. Upon cellular internalization, nanomotors efficiently escape lysosomal entrapment, owing to the proton sponge effect. In acidic tumor microenvironments, sustained release of Ca 2+, Cu 2+, hydrogen peroxide (H 2 O 2 ), and hesperidin occurs, triggering a cascade of therapeutic effects. Notably, Cu 2+ and H 2 O 2 engage in an amplified Fenton-type reaction, yielding abundant hydroxyl radicals. Further, intracellular Cu 2+ accumulation induces ROS overproduction and dihydrolipoamide s-acetyltransferase heterodimerization, resulting in cuproptosis. Intriguingly, hesperidin and excessive ROS synergistically facilitate intracellular Ca 2+ accumulation, leading to calcification, mitochondrial dysfunction, and ROS imbalance, ultimately inducing tumor cell death. Moreover, these self-propelled nanomotors demonstrate superior tumor penetration and accumulation, as evidenced by robust antitumor efficacy in both in vitro and in vivo studies. Collectively, the self-propelled nanomotor system represents a promising method for improving intratumoral delivery and ROS generation, thereby enhancing the therapeutic outcomes of chemodynamic therapy.