Folate-Targeted Liposomal Delivery of a Ru(II)-Based Photosensitizer for Photodynamic Tumor Therapy via Pyroptosis Induction.

Pyroptosis has emerged as a promising antitumor strategy offering unique advantages in overcoming apoptosis resistance and activating antitumor immunity. However, the development of drugs capable of achieving spatiotemporally controlled pyroptosis remains a challenge. Herein, we engineered a folate-targeted liposomal nanoplatform to deliver a Ru(II) complex photosensitizer (Ru-Thi@Lipo-FA) for pyroptosis-mediated photodynamic therapy. The Ru(II) complex (Ru-Thi), acting as a photosensitizer, can produce singlet oxygen and superoxide anions and facilitate the photocatalytic oxidation of NADH through multiple mechanisms to kill tumor cells under white light irradiation. Additionally, we encapsulated the complex within folic acid-modified liposomes, which markedly boosted cellular uptake efficiency and tumor targeting, leading to improved therapeutic effects. Mechanistic investigations demonstrated that light-triggered reactive oxygen species generation activates the caspase-3/GSDME-mediated pyroptosis pathway. This study demonstrated a rationally designed, targeted nanoplatform that utilizes a multifunctional Ru(II)-based photosensitizer and induces pyroptosis, providing a viable approach to improve the efficacy of tumor photodynamic therapy.