Extracellular Vesicle-Based Nucleic Acid Delivery: Current Advances and Future Perspectives in Cancer Therapeutic Strategies

Abstract

Extracellular vesicles (EVs) are sophisticated and sensitive messengers released by cells to communicate with and influence distant and neighboring cells via selective transfer of bioactive content, including protein lipids and nucleic acids. EVs have therefore attracted broad interest as new and refined potential therapeutic systems in many diseases, including cancer, due to their low immunogenicity, non-toxicity, and elevated bioavailability. They might serve as safe and effective vehicles for the transport of therapeutic molecules to specific tissues and cells. In this review, we focus on EVs as a vehicle for gene therapy in cancer. We describe recent developments in EV engineering to achieve efficient intracellular delivery of cancer therapeutics and avoid off-target effects, to provide an overview of the potential applications of EV-mediated gene therapy and the most promising biomedical advances.

Coincubation as miR-Loading Strategy to Improve the Anti-Tumor Effect of Stem Cell-Derived EVs

“…Engineered co-incubated HLSC-EVs efficiently delivered microRNAs, which were indeed protected by RNase, promoting microRNA-specific functions while maintaining the desired effect of naïve EVs on rCSC. The ability of EVs to bind and transport active RNA and DNA species on their surface is a well-known phenomenon [ 1 , 4 ]. In particular, EVs circulating in serum and present in other biological fluids contain within their corona surface-bound nucleic acids that are considered contaminants.…”

“…Therefore, the interest for the exploitation of EVs as therapeutic tool is rapidly increasing [ 2 ]. Indeed, EVs appear a highly efficient delivery system, as compared to naked molecules, as they protect the cargo from degradation by RNases and proteases [ 3 , 4 ]. Moreover, in comparison to synthetic liposomes, EVs might display an increased efficacy since, being a natural cell derived product, they show reduced clearance by the macrophagic system, low immunogenicity and ability to deliver nucleic-acid-based therapeutics across biological barriers [ 5 , 6 ].…”

“…A great deal of effort has been, therefore, dedicated to the pharmacological exploitation of EVs as carriers of specific cargo of interest [ 7 ]. In particular, EV engineering with RNA species has been proposed for different therapeutic applications, ranging from anti-tumor strategies to vaccination [ 4 , 8 , 9 ]. Different technical approaches for EV loading include the option to modify the originating cell, typically by transfection, or to directly load isolated EVs using electroporation [ 4 ].…”

“…In particular, EV engineering with RNA species has been proposed for different therapeutic applications, ranging from anti-tumor strategies to vaccination [ 4 , 8 , 9 ]. Different technical approaches for EV loading include the option to modify the originating cell, typically by transfection, or to directly load isolated EVs using electroporation [ 4 ]. The approach of direct EV loading might be of particular interest in those contexts where the delivery of the identified cargo represents the main mechanism of action of the therapeutic preparation.…”

Glycosylation of Cancer Extracellular Vesicles: Capture Strategies, Functional Roles and Potential Clinical Applications

“…EVs are composed of a phospholipid bilayer that provides protection to their cargo against degradation by the proteases and nucleases present in the external environment [ 106 , 107 ]. EVs encapsulate several molecules, including cytosolic and cytoskeletal proteins as well as enzymes and nucleic acids (mRNA, miRNA, tRNA, rRNA, DNA) [ 108 , 109 , 110 ]. The surface of the EVs is composed of lipids (ceramide, cholesterol, phosphatidylserine and sphingomyelin) and proteins (transmembrane proteins, antigen presenters and adhesion molecules) [ 1 ].…”