Ultrasound‐Responsive Lipid Nanosonosensitizers with Size Reduction and NO Release: Synergistic Sonodynamic‐Chemo‐Immunotherapy for Pancreatic Tumors

Pancreatic cancer (PC) remains difficult to treat due to its dense extracellular matrix (ECM), immunosuppressive tumor microenvironment (TME), and deep‐seated anatomy. To address these challenges, we developed IR&ZnPc@LNP‐NO, an ultrasound (US)‐responsive lipid nanosonosensitizer that synergizes sonodynamic therapy (SDT), chemotherapy, and immunotherapy for orthotopic PC. IR&ZnPc@LNP‐NO undergoes three key US‐activated responses: (1) size reduction, (2) controlled release of irinotecan (IR) and nitric oxide (NO), and (3) generation of reactive oxygen species (ROS). Under low‐dose US, IR&ZnPc@LNP‐NO reduces in size (from ~120 nm to ~40 nm), enhancing tumor penetration, and releases NO to remodel the TME by normalizing vasculature and degrading ECM. This enhances nanosonosensitizers accumulation and cytotoxic T cells (CTLs) infiltration. High‐dose US irradiation triggers the generation of cytotoxic ROS, which, in combination with IR‐mediated chemotherapy, induces immunogenic cell death (ICD) and enhances antitumor immunity. Additionally, combining IR&ZnPc@LNP‐NO with PD‐L1 antibody (αPD‐L1) immunotherapy significantly prolongs survival in orthotopic PC models. The cascade strategy—size reduction, TME remodeling, and multimodal therapy—effectively overcomes stromal and immunosuppressive barriers, offering a robust platform for treating deep‐seated PC.