Ultrasound‐Responsive Lipid Nanosonosensitizers with Size Reduction and NO Release: Synergistic Sonodynamic‐Chemo‐Immunotherapy for Pancreatic Tumors
Abstract
Abstract 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.
Article Details
Authors (13)
Leyi Fang
State Key Laboratory of Analytical Chemistry for Life Science, Department of General Surgery & Pathology, Nanjing Drum Tower Hospital, School of Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC)
Wenhui Zeng
Yili Liu
State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, 163 Xianlin Road, Nanjing 210023, China
Yinxing Miao
State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering
Chunmei Lu
State Key Laboratory of Analytical Chemistry for Life Science, Department of General Surgery & Pathology, Nanjing Drum Tower Hospital, School of Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC)
Zhonghan Xu
State Key Laboratory of Analytical Chemistry for Life Science, Department of General Surgery & Pathology, Nanjing Drum Tower Hospital, School of Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC)
Sensen Zhou
MOE Key Laboratory of High-Performance Polymer Materials and Technology and Department of Polymer Science & Engineering College of Chemistry & Chemical Engineering
Qi Xue
Department of Entomology, The Connecticut Agricultural Experiment Station
Yitong Xu
Xiqun Jiang
MOE Key Laboratory of High-Performance Polymer Materials and Technology and Department of Polymer Science & Engineering College of Chemistry & Chemical Engineering
Jingjuan Xu
Yan Zhang
Deju Ye
State Key Laboratory of Analytical Chemistry for Life Science, Department of General Surgery & Pathology, Nanjing Drum Tower Hospital, School of Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC)