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

Abstract 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.