Abstract
Gene therapy is a therapeutic strategy of delivering foreign genetic material (encoding for an important protein) into a patient’s target cell to replace a defective gene. Nucleic acids are embedded within the adeno-associated virus (AAVs) vectors; however, preexisting immunity to AAVs remains a significant concern that impairs their clinical application. Extracellular vesicles (EVs) hold great potential for therapeutic applications as vectors of nucleic acids due to their endogenous intercellular communication functions through their cargo delivery, including lipids and proteins. So far, small RNAs (siRNA and micro (mi)RNA) have been mainly loaded into EVs to treat several diseases, but the potential use of EVs to load and deliver exogenous plasmid DNA has not been thoroughly described. This review provides a comprehensive overview of the principal methodologies currently employed to load foreign genetic material into EVs, highlighting the need to find the most effective strategies for their successful clinical translation.
Highlights
Nucleic acid-based therapies are rapidly evolving in preclinical and clinical trials for several genetic diseases [1,2,3]
The classification of extracellular vesicles (EVs) is continuously evolving [40], they generally are classified on their biogenesis and release pathways, such as exosomes (Exo) (~40 to 160-nm in diameter) [44,45]; ectosomes [46]; or shedding microvesicles (SMVs), apoptotic blebs (ABs) (1 to 5-mm in diameter) [47], and other EVs subsets [46], generating a heterogeneous group of components able to redistribute their biological cargo into the entire organism
The discrepancies emerged concerning the content of different part-genomic DNA [112] and carrying and deliver nucleic acids to recipient cells depending on the EV subsets urge studies aimed at understanding whether the plasmid DNA loading could vary in different subsets of EVs
Summary
Nucleic acid-based therapies are rapidly evolving in preclinical and clinical trials for several genetic diseases [1,2,3]. Other important AAV-associated limitations, like their small DNA packaging size [35,36,37], the complications of finding the optimal tropism [38], and the gene expression-related slow onset [39], still represent issues and hurdles that impede their broad clinical adoptions in other areas Driven by these limitations, an alternative and efficient loading and delivery system of exogenous nucleic acid remains an ongoing challenge. EVs are formed in endosomal compartments and secreted after fusion with the plasma membrane by most cell types [41,42] They can mediate and transmit a variety of intercellular signaling molecules packaging biological cargo, including nucleic acids, small RNAs (sRNAs), proteins, and lipids altering the gene expression, proliferation, and differentiation of recipient cells during physiological and pathological conditions [43]. The present review gathers the main methodologies currently employed to load foreign genetic material into EVs, the advantages and disadvantages associated with each methodology, and raises questions still unanswered, highlighting the importance of further explorations to optimize the loading strategies in these endogenous vectors as a new tool of the delivery system of foreign genetic materials
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