%0 Journal Article
%T Membrane Fusion-Mediated Loading of Therapeutic siRNA into Exosome for Tissue-Specific Application.
%A Xie M
%A Wu Y
%A Zhang Y
%A Lu R
%A Zhai Z
%A Huang Y
%A Wang F
%A Xin C
%A Rong G
%A Zhao C
%A Jiang K
%A Zhou X
%A Zhou X
%A Zhu X
%A Hong J
%A Zhang C
%J Adv Mater
%V 36
%N 33
%D 2024 Aug 18
%M 38889294
%F 32.086
%R 10.1002/adma.202403935
%X 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.