Branched Polymer‐Based Redox/Enzyme‐Activatable Photodynamic Nanoagent to Trigger STING‐Dependent Immune Responses for Enhanced Therapeutic Effect

Abstract Immune response in the tumor microenvironment (TME) is an essential therapeutic factor for antitumor therapy. Herein, to improve immunostimulatory effects, photodynamic therapy (PDT) is combined with AZD2281 to trigger the stimulator of interferon genes (STING)‐dependent immune responses. A synthetic branched polymer‐pyropheophorbide a (Ppa) conjugate (BGSSP) is designed and developed in response to redox/cathepsin B of the TME. This conjugate with a unique structure and a large molecular weight (MW) can self‐assemble into a compact structure via hydrophilic and hydrophobic forces, inducing self‐quenching of conjugated Ppa. AZD2281 is encapsulated in BGSSP to obtain a TME‐activatable photodynamic nanoagent, AZD@BGSSP. AZD@BGSSP with a stable assembly structure accumulates effectively in tumors and enters lysosomes through endocytosis pathways. Polymer degradation, Ppa activation, and AZD2281 release are achieved after exposure of AZD@BGSSP to highly expressed cathepsin B and glutathione in tumor cells. After laser irradiation, AD2281 inhibits the repair of damaged DNA caused by ROS from PDT and promotes generation of cytosolic DNA, which activates the cGAS‐STING pathway and further induces interferons‐mediated immune responses and a long‐term immune memory effect for immunotherapy. This nanoagent opens a new door to combination PDT and immune response for anti‐cancer treatment.