Abstract：
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.
摘要：
将寡核苷酸治疗剂组织特异性递送到肝脏之外仍然是核酸药物开发中的关键挑战。为了解决这个问题，利用外泌体作为新型载体已成为有效核酸药物递送的有希望的方法。然而,当前基于外泌体的递送系统在其临床应用中仍然面临多个障碍。在这里，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递送。作为一个概念证明,我们成功地将包封抗NFKBIZsiRNA的脂质体与角膜上皮细胞(CEC)来源的外泌体融合,形成用于治疗干眼病(DED)的HEV构建体.具有从外泌体继承的归巢特征，我们携带siRNA的HEV可以靶向其亲本细胞,并有效地将siRNA有效载荷递送至角膜.随后，NFKBIZ基因沉默显著减少眼表促炎细胞因子分泌，重塑了它的炎症微环境，并最终在DED小鼠模型中获得优异的治疗效果。作为一个多功能平台，我们的具有靶向能力的杂交外泌体和设计的治疗性siRNA可能在各种疾病治疗中具有巨大潜力.本文受版权保护。保留所有权利。
