Nanoscale Donor-Acceptor Covalent Organic Frameworks for Mitochondria-Targeted Sonodynamic Therapy and Antitumor Immunity.

Sonodynamic therapy (SDT) based on O2-dependent type II sonosensitizers (SSs) is limited by the hypoxic tumor microenvironment and aggregation-induced quenching (AIQ) of SSs. Type I SSs can generate reactive oxygen species (ROS) with reduced O2 dependence, but their efficacy is still constrained by the high electron-hole recombination rates and low ROS yields. Here, we report the synthesis of a novel two-dimensional nanoscale covalent organic framework (nCOF), Td-Pc, for mitochondria-targeted type I/II SDT. Td-Pc is constructed from staggered zinc-phthalocyanine tetra-anhydride (Pc) units and 4,4'-(thiazolo[5,4-d]thiazole-2,5-diyl)dianiline linkers, forming a donor-acceptor nCOF structure. This structural arrangement significantly alleviates the AIQ of Pc, enhances acoustic electron dissociation and transport, and promotes tumor accumulation. Consequently, Td-Pc enables efficient ROS generation throughout tumor tissues via both type I and II SDT mechanisms. The resulting mitochondrial oxidative stress induces immunogenic cancer cell pyroptosis and upregulates PD-L1 expression. When combined with an anti-PD-L1 monoclonal antibody, Td-Pc-mediated SDT elicits a robust antitumor immune response, leading to effective regression of orthotopic pancreatic ductal adenocarcinoma and bilateral triple-negative breast cancer without causing side effects.