2. Academic Validation
  3. Pyroptotic-Spatiotemporally Selective Delivery of siRNA against Pyroptosis and Autoimmune Diseases

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

  • Adv Mater. 2024 Jul 30:e2407115. doi: 10.1002/adma.202407115.
Zongyou Pan 1 2 3 4 5 6,  Kaiwang Xu 1 2 3 4,  Guanrui Huang 7,  Haoran Hu 8,  Huang Yang 9 10,  Haotian Shen 7,  Kaijie Qiu 1 2 3 4,  Canlong Wang 1 2 3 4,  Tengjing Xu 1 2 3 4,  Xinning Yu 1 2 3 4,  Jinhua Fang 1 2 3 4,  Jiajie Wang 1 2 3 4,  Yunting Lin 1 2 3 4,  Jiacheng Dai 1 2 3 4,  Yuting Zhong 1 2 3 4,  Hongyun Song 1 2 3 4,  Sunan Zhu 1 2 3 4,  Siheng Wang 1 2 3 4,  Zhuxing Zhou 1 2 3 4,  Chuyue Sun 11,  Zhaopeng Tang 12,  Shiyao Liao 13,  Guang Yang 1 2 3 4,  Zhiyuan You 14,  Xuesong Dai 1 2 3 4,  Zhengwei Mao 9 10
Affiliations

Affiliations

  • 1 Department of Orthopedic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.
  • 2 Orthopedics Research Institute, Zhejiang University, Hangzhou, 310009, China.
  • 3 Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, 310009, China.
  • 4 Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, 310009, China.
  • 5 Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
  • 6 Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
  • 7 Department of Orthopedic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.
  • 8 Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, 999077, China.
  • 9 Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.
  • 10 MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, China.
  • 11 Department of Otorhinolaryngology, Head and Neck Surgery, Taihe Hospital of Traditional Chinese Medicine, Anhui University of Chinese Medicine, Fuyang, 236000, China.
  • 12 Department of Orthopedic Surgery, Gansu Provincial Hospital of Traditional Chinese Medicine, Lanzhou, 730050, China.
  • 13 Center for Plastic & Reconstructive Surgery, Department of Orthopedics, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, 310014, China.
  • 14 Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
PMID: 39081086 DOI: 10.1002/adma.202407115
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.

Keywords

anti‐inflammation; nanomedicine; pyroptosis; responsive delivery; targeted delivery.

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