Abstract
Traditional cancer therapies are constrained by tumor diversity, therapeutic resistance, and side effects, thereby necessitating the development of precise multimodal antitumor strategies. This work reports a relatively high-drug-loading polymeric nanoplatform, PSCT, for combined sonodynamic therapy and chemotherapy. Camptothecin (CPT) and tetracarboxyphenylporphyrin (TCPP) were covalently linked to a polymer and self-assembled into stable nanoparticles of about 140 nm. PSCT enabled efficient co-delivery of both agents and favored tumor accumulation. In the reductive tumor microenvironment, elevated glutathione triggered disulfide cleavage and drug release. Under ultrasound (US) irradiation, TCPP generated ROS, resulting in lipid peroxidation and mitochondrial impairment. RNA-Seq analysis and molecular dynamics simulations indicated that PSCT combined with US reprogrammed a dual cell death network involving apoptosis and ferroptosis, accompanied by increased Cleaved Caspase-3 and decreased GPX4 expression. In CT26 tumor-bearing mice, PSCT showed efficient tumor accumulation and achieved an 85.19% ± 5.25% tumor inhibition rate without obvious systemic toxicity. This nanoplatform synergizes sonodynamic therapy and chemotherapy, overcoming resistance from single-pathway treatments and providing a low-toxicity strategy for the precise management of deep-seated tumors.