Long-acting multiple programmed cell death nanoinducers based on polyunsaturated fatty acid supplemented liposomal photosensitizers for enhanced photodynamic immunotherapy.

Abstract

Photodynamic therapy (PDT) has been investigated for minimal invasive treatment of superficial tumors, but its clinical efficacy is constrained by its immediate light-dependent cytotoxicity, low immunogenicity, and other reasons. Building on the capacity of polyunsaturated fatty acids (PUFAs) to convert short-lived reactive oxygen species into longer-lived, highly cytotoxic lipid radicals, we develop a long-acting liposomal photosensitizer by co-encapsulating chlorin e6 (Ce6) and linoleic acid (LA) with commercial lipids. The resulting LA-Ce6@liposome converts short-lived singlet oxygens to persistent lipid radicals during light exposure, sustaining free LA peroxidation even post-irradiation. Mechanistic studies demonstrate that LA-Ce6@liposome-mediated PDT drives immunogenic ferroptosis and PANoptosis in cancer cells via amplified lipid peroxidation. In preclinical models, this strategy not only inhibits the growth of light-irradiated primary tumors but also activates systemic antitumor immunity, delaying progression of distal metastatic and rechallenged tumors, particularly when synergized with immune checkpoint blockade therapy. This study highlights a streamlined strategy to augment conventional PDT by integrating photosensitizers with PUFAs, offering prolonged tumoradical activity and immune activation.