Activatable Immunoprotease Nanorestimulator for Second Near-Infrared Photothermal Immunotherapy of Cancer

Photothermal immunotherapy is a combinational cancer therapy modality, wherein the photothermal process can noninvasively ablate cancer and efficiently trigger cancer immunogenic cell death to ignite antitumor immunity. However, cancer cells can resist the cytotoxic lymphocyte-mediated antitumor effect via expressing serine protease inhibitory proteins (serpins) to deactivate proteolytic immunoproteases. Herein, we report a smart polymer nanoagonist (SPND) with second near-infrared (NIR-II) phototherapeutic ablation and tumor-specific immunoprotease granzyme B (GrB) restimulation for cancer photothermal immunotherapy. SPND has a semiconducting polymer backbone grafted with a small-molecule inhibitor of serpinB9 (Sb9i) via a glutathione (GSH)-cleavable linker. Once in the tumor, Sb9i can be specifically liberated from SPND to inhibit serpinB9, restimulating the activity of GrB to enhance cancer immunotherapy. Moreover, SPND induces photothermal therapy for direct tumor ablation and immunogenic cancer cell death (ICD) under NIR-II photoirradiation. Therefore, such a smart nanoagonist represents a way toward combination photothermal immunotherapy (PTI).