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To address this issue, exploiting exosomes as a novel carrier has emerged as a promising approach for efficient nucleic acid drug delivery. However, current exosome\u2010based delivery systems still face multiple hurdles in their clinical applications. Herein, this work presents a strategy for constructing a hybrid exosome vehicle (HEV) through a DNA zipper\u2010mediated membrane fusion approach for tissue\u2010specific siRNA delivery. As a proof\u2010of\u2010concept, this work successfully fuses a liposome encapsulating anti\u2010NFKBIZ siRNAs with corneal epithelium cell (CEC)\u2010derived exosomes to form a HEV construct for the treatment of dry eye disease (DED). With homing characteristics inherited from exosomes, the siRNA\u2010bearing HEV can target its parent cells and efficiently deliver the siRNA payloads to the cornea. Subsequently, the NFKBIZ gene silencing significantly reduces pro\u2010inflammatory cytokine secretions from the ocular surface, reshapes its inflammatory microenvironment, and ultimately achieves an excellent therapeutic outcome in a DED mouse model. As a versatile platform, this hybrid exosome with targeting capability and designed therapeutic siRNAs may hold great potential in various disease treatments.<\/jats:p>","DOI":"10.1002\/adma.202403935","type":"journal-article","created":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T14:20:31Z","timestamp":1718720431000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":101,"title":["Membrane Fusion\u2010Mediated Loading of Therapeutic siRNA into Exosome for Tissue\u2010Specific Application"],"prefix":"10.1002","volume":"36","author":[{"given":"Miao","family":"Xie","sequence":"first","affiliation":[{"name":"School of Chemistry and Chemical Engineering Frontiers Science Center for Transformative Molecules Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs Shanghai Jiao Tong University  Shanghai 200240 P. R. 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