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. China.
Department of Ophthalmology, Eye & ENT Hospital, State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, 200031, P. R. China.
Adv Mater. 2024 Aug;36(33):e2403935. doi: 10.1002/adma.202403935. Epub 2024 Jul 1.
Tissue-specific delivery of oligonucleotide therapeutics beyond the liver remains a key challenge in nucleic acid drug development. 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-based 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-mediated membrane fusion approach for tissue-specific siRNA delivery. As a proof-of-concept, this work successfully fuses a liposome encapsulating anti-NFKBIZ siRNAs with corneal epithelium cell (CEC)-derived exosomes to form a HEV construct for the treatment of dry eye disease (DED). With homing characteristics inherited from exosomes, the siRNA-bearing HEV can target its parent cells and efficiently deliver the siRNA payloads to the cornea. Subsequently, the NFKBIZ gene silencing significantly reduces pro-inflammatory 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.
将寡核苷酸治疗药物递送到肝脏以外的组织仍然是核酸药物开发中的一个关键挑战。为了解决这个问题，利用外泌体作为一种新型载体来高效递送核酸药物已经成为一种很有前途的方法。然而，目前基于外泌体的递药系统在其临床应用中仍然面临着多个障碍。在这项工作中，我们提出了一种通过 DNA 拉链介导的膜融合方法构建杂交外泌体载体（HEV）的策略，用于组织特异性 siRNA 递药。作为概念验证，我们成功地将包载抗-NFKBIZ siRNA 的脂质体与角膜上皮细胞（CEC）来源的外泌体融合，形成用于治疗干眼症（DED）的 HEV 构建体。具有外泌体继承的归巢特性，携带 siRNA 的 HEV 可以靶向其亲代细胞，并将 siRNA 有效递送到角膜。随后，NFKBIZ 基因沉默显著减少了眼表的促炎细胞因子分泌，重塑了其炎症微环境，最终在 DED 小鼠模型中实现了极好的治疗效果。作为一个多功能平台，这种具有靶向能力和设计治疗性 siRNA 的杂交外泌体可能在各种疾病治疗中具有巨大的潜力。
