Activatable Immunoprotease\nNanorestimulator for Second\nNear-Infrared Photothermal Immunotherapy of Cancer

Abstract

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