Sonoactivated Z‐Scheme Heterojunction for Enhanced Sonodynamic Mitophagy Inhibition and Triple Negative Breast Cancer Treatment

Sonodynamic therapy (SDT) has emerged as a potent therapeutic modality to generate intratumoral toxic reactive oxygen species (ROS) in combating refractory triple-negative breast cancer (TNBC). However, its therapeutic efficacy is compromised due to pro-survival cancer-cell mitophagy to mitigate mitochondrial oxidative damage. Here, an "all-in-one" tumor-therapeutic strategy that integrates nanosonosensitizer-augmented noninvasive SDT with mitophagy inhibition is reported. This is achieved using a rationally constructed sonoactivated liquid Z-scheme heterojunction that connects sonosensitizer PtCu₃ nanocages and mitophagy-blocking sonosensitizer BP nanosheets via an amphipathic organic linker (PEI-PEG₅₀₀₀-C18). The conjugated electron mediator (M, Cp*Rh(phen)Cl) is strategically positioned between the 2 sonosensitizers to facilitate electron transfer. This M-based Z-scheme configuration prolongs the separation of sonoactivated electron-hole pairs, leading to efficient ROS generation upon ultrasound stimulation. Importantly, Cu²⁺ released from PtCu₃ expedites BP degradation by reducing phosphorus vacancy formation energy, improving the overall biodegradability of BP-M-PtCu₃ and favoring phosphate ions production. These ions elevate lysosomal pH, inhibiting the hydrolysis of damaged mitochondria within autophagic lysosomes, thus preventing cancer cell self-preservation under oxidative stress and effectively eliminating TNBC. It is believe that the M-based sonoactivated Z-scheme heterojunction will be a promising sonosensitizer structure, and the sonodynamic mitophagy inhibition strategy offers valuable prospects for cancer treatment.