Synergizing Ferroptosis Suppressor Protein 1 Gene Silencing and Photodynamic Therapy Based on Photosensitive Lipid Nanoparticles for Colon Cancer Immunotherapy.

Metastasis and immune escape play crucial roles in the progression of colon cancer. Current chemotherapy and immunotherapy treatments have limited effectiveness in reversing the immunologically cold microenvironment. Therefore, it is essential to investigate efficient strategies to enhance the antitumor immunity. In this study, ferroptosis suppressor protein 1 (FSP1) siRNA and photosensitizer Verteporfin were incorporated into the lipid nanoparticle (LNP) formulation for synergistic colon cancer immunotherapy. We first screened the photosensitive LNP formulations using different types of light-responsive small molecules. The selected photosensitive LNPs were further optimized by modulating surface properties to improve cellular uptake and endosomal escape levels in colon cancer cells. Upon light irradiation, the engineered photosensitive LNPs promoted synergistic ferroptosis by FSP1 gene silencing and oxidative stress, thereby causing immunogenic cell death to stimulate dendritic cell maturation and cytotoxic T lymphocyte response. In a bilateral tumor model, photosensitive LNPs exhibited potent antitumor efficacy and robust immunostimulatory effect upon light irradiation, enabling safe and efficient colon cancer treatment. This study demonstrates a synergistic potential between FSP1 gene silencing and photodynamic therapy, expanding the applications of photosensitive LNPs in clinical cancer treatment.