Nitric Oxide-Producing Multiple Functional Nanoparticle Remodeling Tumor Microenvironment for Synergistic Photodynamic Immunotherapy against Hypoxic Tumor.

The treatment of pancreatic cancer faces significant challenges due to connective tissue hyperplasia and severe hypoxia. Unlike oxygen-dependent Type II photosensitizers, Type I photosensitizers can produce a substantial amount of reactive oxygen species, even under hypoxic conditions, making them more suitable for photodynamic therapy of pancreatic cancer. However, the dense extracellular matrix of pancreatic cancer limits the penetration efficiency of photosensitizers, and the presence of immunosuppressive cells in the tumor microenvironment reduces the therapeutic effect. To address these challenges, we designed the photoimmunotherapeutic M1@PAP nanoparticles composed of Type I photosensitizer and anti-PD-L1 siRNA (siPD-L1), which was encapsulated into M1 macrophage membrane vesicles. In this system, pyropheophorbide-a (PPA) was covalently conjugated to poly-l-arginine (Arg). Notably, it was capable of generating sufficient superoxide anions under hypoxic conditions, thereby functioning as a Type I photosensitizer. Furthermore, Arg acted as a nitric oxide (NO) donor, enhancing the penetration efficiency of the nanophotosensitizer by inhibiting cancer-associated fibroblast (CAF) activation and decomposing the tumor extracellular matrix. Additionally, M1 macrophage membrane vesicles provided active targeting capabilities and reeducated immunosuppressed M2 macrophages. The reversal of immunosuppressive microenvironment further promoted the efficacy of anti-PD-L1 siRNA immunotherapy, showing great potential in synergistic photodynamic immunotherapy against hypoxic pancreatic tumor.