Activatable Cancer Sono‐Immunotherapy using Semiconducting Polymer Nanobodies

Abstract Despite the great promises of sonodynamic therapy (SDT) in combination cancer therapy, its clinical applications are hindered by the “always‐on” pharmacological activities of therapeutic agents and the lack of efficient sonosensitizers. Herein, the development of semiconducting polymers as efficient sonosensitizers and further development of sono‐immunotherapeutic nanobodies (SPN_Ab) for activatable cancer sono‐immunotherapy are reported. Conjugation of anti‐CTLA‐4 antibodies onto the polymer nanoparticles through a ¹O₂‐cleavable linker affords SPN_Ab with relatively low CTLA‐4 binding affinity. Upon sono‐irradiation, SPN_Ab generates ¹O₂ not only to elicit a sonodynamic effect to induce immunogenic cell death, but also to release anti‐CTLA‐4 antibodies and trigger in situ checkpoint blockade. Such a synergistic therapeutic action mediated by SPN_Ab modulates the tumoricidal function of T‐cell immunity by promoting the proliferation of cytotoxic T lymphocytes and depleting immunosuppressive regulatory T cells, resulting in effective tumor regression, metastasis inhibition, durable immunological memory, and prevention of relapse. Therefore, this study represents a proof‐of‐concept sonodynamic strategy using semiconducting polymers for precise spatiotemporal control over immunotherapy.