Ultrasound-Mediated Piezocatalysis Triggers NO Release to Augment Targeted Immunotherapy of Pancreatic Cancer

Although immune checkpoint inhibitor-based immunotherapy has shown clinical efficacy in various cancer types, its efficacy in pancreatic cancer remains limited. This limitation is primarily attributed to the dense stromal tumor microenvironment (TME) and highly immunosuppressive TME of pancreatic cancer. The dense stromal TME forms a physical barrier that severely hinders the penetration and accumulation of therapeutic agents and immune cells. Additionally, it collaborates with the immunosuppressive TME to weaken immune responses against tumors. To overcome these challenges, a piezoelectric nanoparticle system, BTO@BAL, was developed, which combined piezoelectric nanomaterial barium titanate (BTO), a targeting peptide, and an amphiphilic prodrug molecule. The prodrug molecule is composed of a small-molecule PD-L1 inhibitor (BMS1166) and a nitric oxide (NO) donor (Arg)9, linked by a thioketal bond. Upon ultrasound (US)-triggered piezocatalysis, BTO continuously generated reactive oxygen species (ROS) in the hypoxic TME. On the one hand, ROS oxidized (Arg)9 to release NO, which degraded the dense stromal barrier of pancreatic cancer, remodeled the TME, improved tumor mechanical properties, and reduced stiffness. Combined with the targeted peptide, this strategy synergistically improved drug delivery efficiency. Furthermore, the combined action of ROS and NO enhanced the immunogenicity of pancreatic cancer, promoting the activation and maturation of local dendritic cells, thereby strengthening antitumor immune responses. On the other hand, ROS induced thioketal bond cleavage to release BMS1166, effectively down-regulating PD-L1 expression on KPC cells, reshaping the immunosuppressive TME of pancreatic cancer, and further amplifying the efficacy of immunotherapy. This strategy integrated US-triggered piezocatalysis with gas therapy, greatly enhancing pancreatic cancer immunotherapy and offering a theoretical foundation for developing tumor theranostic platforms.