Pan Zongyou, Xu Kaiwang, Huang Guanrui, Hu Haoran, Yang Huang, Shen Haotian, Qiu Kaijie, Wang Canlong, Xu Tengjing, Yu Xinning, Fang Jinhua, Wang Jiajie, Lin Yunting, Dai Jiacheng, Zhong Yuting, Song Hongyun, Zhu Sunan, Wang Siheng, Zhou Zhuxing, Sun Chuyue, Tang Zhaopeng, Liao Shiyao, Yang Guang, You Zhiyuan, Dai Xuesong, Mao Zhengwei
Department of Orthopedic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.
Orthopedics Research Institute, Zhejiang University, Hangzhou, 310009, China.
Adv Mater. 2024 Sep;36(38):e2407115. doi: 10.1002/adma.202407115. Epub 2024 Jul 30.
Small-interfering RNAs (siRNAs) offer promising prospects for treating pyroptosis-related autoimmune diseases. However, poor stability and off-target effects during in vivo transportation hinder their practical clinical applications. Precision delivery and adaptive release of siRNAs into inflamed tissues and immune cells could unleash their full therapeutic potential. This study establishes a pyroptotic-spatiotemporally selective siRNA delivery system (PMRC@siGSDME) that selectively targets inflammatory tissues, responds to pyroptosis, and exhibits remarkable therapeutic efficacy against various autoimmune diseases. Novel hybrid nanovesicles (NVs) are designed as a combination of pyroptotic macrophage membranes (PMs) and R8-cardiolipin-containing nanovesicles (RC-NVs). Evidence provides that PM-derived proteins involved in cell-cell interactions and membrane trafficking may contribute to the specificity of NVs to inflammatory tissue. In addition, cardiolipin anchored in the hybrid NVs increases its affinity for activated gasdermin E (GSDME) and achieves pyroptosis-adaptive release of siGSDME for the spatiotemporally selective suppression of immune responses. More importantly, PMRC@siGSDME displays significant anti-inflammatory and therapeutic effects in multiple mouse autoimmune disease models, including arthritis and inflammatory bowel disease (IBD). Collectively, an innovative siRNA delivery strategy precisely tailored for pyroptotic cells has been developed, paving the way for new treatments for autoimmune inflammatory diseases with minimal side effects and wide clinical applicability.
小分子干扰RNA（siRNAs）为治疗与细胞焦亡相关的自身免疫性疾病提供了广阔前景。然而，其在体内运输过程中稳定性差和脱靶效应阻碍了它们的实际临床应用。将siRNAs精确递送至炎症组织和免疫细胞并实现适应性释放，可充分发挥其治疗潜力。本研究建立了一种细胞焦亡时空选择性siRNA递送系统（PMRC@siGSDME），该系统可选择性靶向炎症组织，对细胞焦亡作出反应，并对各种自身免疫性疾病表现出显著的治疗效果。新型混合纳米囊泡（NVs）被设计为由细胞焦亡巨噬细胞膜（PMs）和含R8-心磷脂的纳米囊泡（RC-NVs）组成。有证据表明，参与细胞间相互作用和膜运输的PM衍生蛋白可能有助于NVs对炎症组织的特异性。此外，锚定在混合NVs中的心磷脂增加了其对活化的gasdermin E（GSDME）的亲和力，并实现了siGSDME的细胞焦亡适应性释放，用于时空选择性抑制免疫反应。更重要的是，PMRC@siGSDME在多种小鼠自身免疫性疾病模型中，包括关节炎和炎症性肠病（IBD），显示出显著的抗炎和治疗效果。总的来说，已经开发出一种专门为细胞焦亡细胞量身定制的创新siRNA递送策略，为副作用最小且临床适用性广泛的自身免疫性炎症疾病的新治疗方法铺平了道路。
