journal article·2024-09Open access

Pyroptotic‐Spatiotemporally Selective Delivery of siRNA against Pyroptosis and Autoimmune Diseases

Zongyou Pan, Kaiwang Xu, Guanrui Huang, Haoran Hu, Huang Yang, Haotian Shen, Kaijie Qiu, Canlong Wang, Tengjing Xu, Xinning Yu, Jinhua Fang, Jiajie Wang, Yunting Lin, Jiacheng Dai, Yuting Zhong, Hongyun Song, Sunan Zhu, Siheng Wang, Zhuxing Zhou, Chuyue Sun, Zhaopeng Tang, Shiyao Liao, Guang Yang, Zhiyuan You, Xuesong Dai, Zhengwei Mao

Advanced Materials· Volume 36· Issue 38

Abstract

Abstract 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.
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Research context

OpenAlex topics: Inflammasome and immune disorders · Kawasaki Disease and Coronary Complications · Extracellular vesicles in disease

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Orthopedic Surgery Second Affiliated Hospital School of Medicine Zhejiang University Hangzhou 310009 China

Orthopedics Research Institute Zhejiang University Hangzhou 310009 China

Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province Hangzhou 310009 China

Clinical Research Center of Motor System Disease of Zhejiang Province Hangzhou 310009 China

Division of Gastroenterology Hepatology and Endoscopy Brigham and Women's Hospital Harvard Medical School Boston MA 02115 USA

Department of Orthopedic Surgery First Affiliated Hospital School of Medicine Zhejiang University Hangzhou 310009 China

Department of Pathology The University of Hong Kong Queen Mary Hospital Pokfulam Hong Kong 999077 China

Department of Hepatobiliary and Pancreatic Surgery Second Affiliated Hospital School of Medicine Zhejiang University Hangzhou 310009 China

MOE Key Laboratory of Macromolecular Synthesis and Functionalization Department of Polymer Science and Engineering Zhejiang University Hangzhou 310027 China

Department of Otorhinolaryngology Head and Neck Surgery Taihe Hospital of Traditional Chinese Medicine Anhui University of Chinese Medicine Fuyang 236000 China

Department of Orthopedic Surgery Gansu Provincial Hospital of Traditional Chinese Medicine Lanzhou 730050 China

Center for Plastic & Reconstructive Surgery Department of Orthopedics Zhejiang Provincial People's Hospital Hangzhou Zhejiang 310014 China

Department of Immunology St. Jude Children's Research Hospital Memphis TN 38105 USA

Funding

National Natural Science Foundation of China

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