Janus TiO₂-CoO_X heterojunction enabling sonodynamic driving multi-pathway cell death for enhanced immune activation

Tumor heterogeneity induces resistance of programmed cell death (PCD), together with a highly immunosuppressive tumor microenvironment (TME), collectively constraining the efficacy of cancer therapies. Herein, a Janus TiO₂-CoO_X@PEG nanoplatform featuring a Z-scheme heterojunction was developed as a novel sonosensitizer, enabling efficient ultrasound-induced charge separation to boost sonodynamic therapy (SDT) activity. Moreover, the obtained TiO₂-CoO_X@PEG was endowed with multienzyme activity, including glutathione (GSH) oxidase- and catalase-like activities, which could regulate TME (e.g., relieve hypoxia), amplify oxidative stress, and collaboratively break intracellular redox homeostasis, thereby dismantling tumor defense barriers. More interestingly, upon ultrasound (US) irradiation, SDT together with chemodynamic therapy (CDT) was found to concurrently activate three programmed cell death pathways, i.e., apoptosis, ferroptosis, and pyroptosis to overcome tumor treatment resistance. This multiple death-pathway efficiently induced immunogenic cell death (ICD), promoting the release of damage-associated molecular patterns (DAMPs) and inflammatory cytokines. As a result, the in vivo tumor growth was significantly suppressed and the immunosuppressive TME was remodeled, as characterized by tumor-associated macrophages (TAMs) polarizing towards the M1 phenotype, maturation of dendritic cells (DCs), infiltration of abundant cytotoxic T lymphocytes (CTLs), and depletion of regulatory T cells (Tregs), which ultimately impeded the formation of distant lung metastases. Collectively, this work presents a sonodynamic-immunotherapeutic synergistic strategy based on Janus heterojunction nanoparticles to induce multi-pathway cell death and immune activation, offering a promising solution to overcome treatment resistance and achieve sustained systemic antitumor immunity.