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 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.