Abstract
Extracellular vesicles (EVs), endogenous nanocarriers of proteins, lipids, and genetic material, have been harnessed as intrinsic delivery vectors for nucleic acid therapies. EVs are nanosized lipid bilayer bound vesicles released from most cell types responsible for delivery of functional biologic material to mediate intercellular communication and to modulate recipient cell phenotypes. Due to their innate biological role and composition, EVs possess several advantages as delivery vectors for nucleic acid based therapies including low immunogenicity and toxicity, high bioavailability, and ability to be engineered to enhance targeting to specific recipient cells in vivo. In this review, the current understanding of the biological role of EVs as well as the advancements in loading EVs to deliver nucleic acid therapies are summarized. We discuss the current methods and associated challenges in loading EVs and the prospects of utilizing the inherent characteristics of EVs as a delivery vector of nucleic acid therapies for genetic disorders.
Highlights
Nucleic acid-based therapeutics, small interfering RNA, microRNA, double stranded DNA and antisense oligonucleotides (ASOs) are promising disease altering modalities because they target disease causing genes in a sequence specific manner
In this review we focus on Extracellular vesicles (EVs) loading and mediated delivery of small interfering RNA (siRNA), ASO, and miRNA (Fig. 1) (See more reviews on loading of alternative cargoes into EVs in [10,11,12,13,14])
20-80% knockdown of target gene dose-dependent silencing of Htt mRNA, up to 75% reduction and HTT protein up to 68% reduction and bilateral silencing of up to 35% of Huntingtin mRNA. 18-fold Increase in dystrophin expression in muscular dystrophy mouse model compared to naked ASO 50% knockdown of target gene
Summary
Nucleic acid-based therapeutics, small interfering RNA (siRNA), microRNA (miRNA), double stranded DNA (dsDNA) and antisense oligonucleotides (ASOs) are promising disease altering modalities because they target disease causing genes in a sequence specific manner. The specificity of these therapies is a targeted approach for treatment of various diseases, including hereditary amyloidogenic transthyretin amyloidosis, spinal muscular atrophy, Duchenne’s Muscular Dystrophy Disease, amyotrophic lateral sclerosis, among others [1,2,3]. RNA interference (RNAi), siRNA and miRNA, knocks down target gene expression by binding to specific mRNA for 1) degradation or 2) repression [1, 2, 4, 15, 16]. 1) Restore mRNA reading frames. 2) Promote inclusion of skipped exons 3) introduce an out-of-frame deletion
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