Song Yang, Xu Shuyu, Zhang Jinxia, Zhang Tianjiao, Wu Ruiqi, Feng Guotao, Tang Qingshuang, Yu Zexing, Shi Xue, Li Xin, Li Ling, Zhang Niya, Ge Huiyu, Liang Xiaolong
Departments of Ultrasound Medicine Beijing Chaoyang Hospital, Capital Medical University, North Road 8, Gongti, Chaoyang, Beijing 100020, China.
State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Ultrasound, Peking University Third Hospital, Beijing 100191, China.
ACS Nano. 2025 Sep 16;19(36):32654-32673. doi: 10.1021/acsnano.5c10301. Epub 2025 Sep 4.
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.
尽管基于免疫检查点抑制剂的免疫疗法在多种癌症类型中已显示出临床疗效，但其在胰腺癌中的疗效仍然有限。这种局限性主要归因于胰腺癌致密的基质肿瘤微环境（TME）和高度免疫抑制的TME。致密的基质TME形成了一个物理屏障，严重阻碍了治疗药物和免疫细胞的渗透与聚集。此外，它与免疫抑制性TME协同作用，削弱针对肿瘤的免疫反应。为了克服这些挑战，开发了一种压电纳米颗粒系统BTO@BAL，它结合了压电纳米材料钛酸钡（BTO）、靶向肽和两亲性前药分子。前药分子由小分子PD-L1抑制剂（BMS1166）和一氧化氮（NO）供体（精氨酸）9通过硫酮键连接而成。在超声（US）触发的压电催化作用下，BTO在缺氧的TME中持续产生活性氧（ROS）。一方面，ROS氧化（精氨酸）9以释放NO，NO降解了胰腺癌的致密基质屏障，重塑了TME，改善了肿瘤力学性能并降低了硬度。结合靶向肽，该策略协同提高了药物递送效率。此外，ROS和NO的联合作用增强了胰腺癌的免疫原性，促进了局部树突状细胞的活化和成熟，从而增强了抗肿瘤免疫反应。另一方面，ROS诱导硫酮键断裂以释放BMS1166，有效下调KPC细胞上PD-L1的表达，重塑胰腺癌的免疫抑制性TME，并进一步放大免疫疗法的疗效。该策略将US触发的压电催化与气体疗法相结合，极大地增强了胰腺癌免疫疗法，并为开发肿瘤诊疗平台提供了理论基础。
