Biodegradable NIR‐II Pseudo Conjugate Polymeric Nanoparticles Amplify Photodynamic Immunotherapy via Alleviation of Tumor Hypoxia and Tumor‐Associated Macrophage Reprogramming

Abstract Photodynamic therapy (PDT) has achieved great success in cancer treatment. Despite its great promise, the efficacy of photodynamic immunotherapy can be limited by the hypoxia in solid tumors which is closely related to the abnormal tumor vasculature. These abnormal vasculatures are a hallmark of most solid tumors and facilitate immune evasion. Therefore, tumor vascular normalization is developed as a promising strategy to overcome tumor hypoxia, resulting in improved cancer therapy. Here, a NIR‐II bio‐degradable pseudo‐conjugate polymer (PSP)‐based photodynamic polymer is designed to deliver a vascular normalization agent, i.e., regorafenib (Reg) in nanoparticles (NP‐PDT@Reg). NP‐PDT@Reg under 808 nm laser irradiation (NP‐PDT@Reg + L) can efficiently release Reg to improve the tumor hypoxia via vascular normalization, making more NP‐PDT@Reg and oxygen enter the tumors. Moreover, NP‐PDT@Reg + L can further result in generation of more reactive oxygen species (ROS) to eradicate tumor cells while inducing immunogenic cell death (ICD) to activate anti‐tumor immune responses. In addition, Reg can reprogram TAM from a pro‐tumor M2 phenotype to a tumor‐killing M1 phenotype as well, thereby reversing the immunosuppressive tumor microenvironment. Taken together, the current study provides an innovative perspective on the development of novel nanomaterials to overcome the limitations in photodynamic immunotherapy.