Wen E, Tian Yu, Fang Mingxiao, Zhang Yuezhou, Zhao Hongyun, Wang Zhigang, Zhang Liang, Li Xingsheng
Precision Medicine Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People's Republic of China.
Department of Critical Care Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People's Republic of China.
ACS Appl Mater Interfaces. 2025 Feb 5;17(5):7521-7538. doi: 10.1021/acsami.4c21010. Epub 2025 Jan 24.
20% acute pancreatitis (AP) develops into severe AP (SAP), a global health crisis, with an increased mortality rate to 30%-50%. Mitochondrial damage and immune disorders are direct factors, which exacerbate the occurrence and progression of AP. So far, mitochondrial and immunity injury in SAP remains largely elusive, with no established treatment options available. Immunomodulation is a promising approach to treat pancreatitis. Herein, we proved that Tuftsin (TN), a vital endogenous immunomodulator, can inhibit SAP, while it is limited by extremely short biological half-life, low bioavailability, and the inconvenience of administration. Nano platform is the positive choice. Interestingly, we found that the activated P2X7 signaling was closely associated with the enhanced pancreatic inflammation via damaging mitochondrial function in SAP. Herein, we engineered a nanoplatform containing a Se-Se bond responsive for ROS to deliver TN, namely, DSPE-Se-Se-MPEG@TN (DSSM@TN), contributing to increases in TN's half-life and bioavailability. We synthesized TN-loaded ROS-responsive DSPE-Se-Se- MPEG@TN liposomes (DSSM@TN NPs) via a one-step emulsification method, which exhibited good biosecurity, high stability, suitable size, favorable ROS responsiveness and biocompatibility, as well as excellent capability for releasing TN during oxidative stress and inflammation environment. Moreover, the Se-Se bond with ROS-responsive ability was first proved to play a vital role for TN-loaded liposomes to enhance its anti-inflammation and antioxidant abilities via targeting damaged mitochondria during SAP progression. Mechanistically, DSSM@TN targeting damaged pancreas simultaneously inhibits mitochondrial dysfunction and inflammation in vivo and vitro via mitochondrial P2X7 signaling-impaired Nrf2/HO-1 signaling-inhibited PINK1/PARKIN pathway. Consequently, such a ROS-responsive immunotherapy nanomedicine targeted mitochondria holds great potential in facilitating substantial clinical progress in SAP treatment.
20%的急性胰腺炎（AP）会发展为重症急性胰腺炎（SAP），这是一个全球性的健康危机，死亡率增至30%-50%。线粒体损伤和免疫紊乱是直接因素，会加剧AP的发生和发展。到目前为止，SAP中的线粒体和免疫损伤在很大程度上仍不清楚，也没有既定的治疗方案。免疫调节是治疗胰腺炎的一种有前景的方法。在此，我们证明了胸腺肽（TN），一种重要的内源性免疫调节剂，可以抑制SAP，但它受到极短的生物半衰期、低生物利用度和给药不便的限制。纳米平台是一个不错的选择。有趣的是，我们发现激活的P2X7信号通路通过破坏SAP中的线粒体功能与胰腺炎症增强密切相关。在此，我们构建了一种含有对活性氧（ROS）有响应的硒-硒键的纳米平台来递送TN，即DSPE-Se-Se-MPEG@TN（DSSM@TN），有助于延长TN的半衰期和提高生物利用度。我们通过一步乳化法合成了负载TN的ROS响应性DSPE-Se-Se-MPEG@TN脂质体（DSSM@TN纳米粒），其具有良好的生物安全性、高稳定性、合适的尺寸、良好的ROS响应性和生物相容性，以及在氧化应激和炎症环境中释放TN的优异能力。此外，首次证明具有ROS响应能力的硒-硒键在负载TN的脂质体通过在SAP进展过程中靶向受损线粒体增强其抗炎和抗氧化能力方面起着至关重要的作用。机制上，DSSM@TN靶向受损胰腺在体内外通过线粒体P2X7信号通路受损的Nrf2/HO-1信号通路抑制的PINK1/PARKIN途径同时抑制线粒体功能障碍和炎症。因此，这种靶向线粒体的ROS响应性免疫治疗纳米药物在推动SAP治疗取得实质性临床进展方面具有巨大潜力。
