Targeted Dual-Responsive Liposomes Co-Deliver Jolkinolide B and Ce6 to Synergistically Enhance the Photodynamic/Immunotherapy Efficacy in Gastric Cancer through the PANoptosis Pathway.

Improving the efficacy of gastric cancer (GC) treatment remains an ongoing challenge. Considering the increasing importance of PANoptosis, a novel form of programmed cell death, the current study integrates photodynamic therapy (PDT) and chemodynamic therapy (CDT) into nanoliposomes. This approach utilizes the ability of photosensitizer Chlorin e6 (Ce6) to generate reactive oxygen species (ROS) and the function of the natural targeting agent Jolkinolide B to activate the PANoptosis molecular switch, inducing the ROS-caspase8/PANoptosis pathway to promote GC cell death. The designed CJP-TiN liposome targets GC via internalizing RGD peptide (iRGD), and demonstrates ROS/pH dual responsiveness in the tumor microenvironment. In vitro and in vivo experiments show effective ROS generation ability under light exposure, killing tumor cells and triggers thioether bond cleavage for dual-controlled drug release. The combined therapy enhances antitumor effect, converting "cold tumors" into "hot tumors," thereby enhancing the success of immunotherapy. The role of CJP-TiN as a PANoptosis inducer in the tumor microenvironment is confirmed, thereby expanding its application potential as a molecularly targeted therapy for GC treatment, and providing a novel perspective for therapeutic strategies.