NaSO Nanoparticles Trigger Antitumor Immunotherapy through Reactive Oxygen Species Storm and Surge of Tumor Osmolarity.

Although more attention has been attracted to the therapy based on reactive oxygen species (ROS) for tumor therapy in recent years, such as photodynamic therapy and chemodynamic therapy, the limited ROS production rate leads to their poor treatment effect owing to the relatively low content of O and HO in tumor microenvironments, confined light penetration depth, strict Fenton reaction conditions (pH 3-4), and so on. Therefore, it is urgent to explore the new agents with highly efficient ROS generation capacity. Herein, we first prepared phospholipid coated NaSO nanoparticles (PNSO NPs) as new ROS generation agents for in situ generating Na and SO through gradual degradation, which can then be changed to toxic SO (a novel reported ROS) and OH regardless of the amount of HO and pH value in the tumor microenvironment (TME). As the generation of a large amount of Na, PNSO NPs can bypass the ion transport rules of cells through endocytosis to deliver large amounts of Na into the cells, resulting in a surge of osmolarity and rapid cell rupture and lysis. Osmotic pressure induced by PNSO NPs will further lead to an unusual manner of cell death: caspase-1-related pyroptosis. Moreover, all of above effects will cause high immunogenic cell death, regulate the immunosuppressed TME, and then activate systemic antitumor immune responses to combat tumor metastasis and recurrence. We believe PNSO NPs will be new and potential ROS generation agents, and this work will broaden the thinking of the exploring of new antitumor nanodrugs.