Synergistic Nucleus-Targeting Photodynamic Therapy and DNA Repair Inhibition to Activate Innate and Adaptive Antitumor Immunity for Amplifying Photoimmunotherapy

Photodynamic therapy (PDT) has received increasing attention because it can induce immunogenic cell death (ICD) and activate the STING pathway. However, the immune response induced by PDT is limited by its poor DNA damage, due to random intracellular distribution of the photosensitizer and the repair mechanism of cells. To this end, a liposomal nanophotosensitizer PNOR, modified with arginylglycylaspartic acid (RGD) peptide on the surface and coloaded with nucleus-targeting photosensitizer Ppa-Nuc and DNA repair inhibitor Olaparib (Ola), is developed to improve photoimmunotherapy. PNOR reveals exceptional nucleus-targeting capability, and nucleus-targeted PDT is demonstrated to induce substantial ICD and robust STING pathway activation in vitro. PNOR effectively enhances dendritic cell maturation and activation of cytotoxic T cells, thus exhibiting remarkable antitumor efficacy in both primary and distant tumors in a bilateral subcutaneous pancreatic tumor model. PNOR represents a promising strategy for improving photoimmunotherapy by inducing efficient DNA oxidative damage to simultaneously activate an innate and adaptive immune response.