Exosome mediated delivery of functional nucleic acid nanoparticles (NANPs)

Senny Nordmeier,Weina Ke,Kirill A Afonin,Victoria Portnoy

doi:10.1016/j.nano.2020.102285

Abstract

RNAi-based technologies have shown biomedical potential; however, safe and efficient delivery of RNA remains a barrier for their broader clinical applications. Nucleic acid nanoparticles (NANPs) programmed to self-assemble and organize multiple therapeutic nucleic acids (TNAs) also became attractive candidates for diverse therapeutic options. Various synthetic nanocarriers are used to deliver TNAs and NANPs, but their clinical translation is limited due to immunotoxicity. Exosomes are cell-derived nanovesicles involved in cellular communication. Due to their ability to deliver biomolecules, exosomes are a novel delivery choice. In this study, we explored the exosome-mediated delivery of NANPs designed to target GFP. We assessed the intracellular uptake, gene silencing efficiency, and immunostimulation of exosomes loaded with NANPs. We also confirmed that interdependent RNA/DNA fibers upon recognition of each other after delivery, can conditionally activate NF-kB decoys and prevent pro-inflammatory cytokines. Our study overcomes challenges in TNA delivery and demonstrates future studies in drug delivery systems.

Highlights

Nucleic acid nanoparticles (NANPs) are modular nanoscaffolds composed of multiple oligonucleotides programmed to self-assemble into precise 3D structures with well-defined properties [1,2,3,4]
Exosome loading with NANPs of various sizes can be challenging and numerous methods have been developed to efficiently facilitate the transfection
In order to load the cube, ring, and fiber NANPs into exosomes, ExoFect reagent forms a complex with the nucleic acids

Summary

Introduction

Nucleic acid nanoparticles (NANPs) are modular nanoscaffolds composed of multiple oligonucleotides programmed to self-assemble into precise 3D structures with well-defined properties [1,2,3,4]. Designed NANPs can be further decorated with cocktails of therapeutic nucleic acids (TNAs), which may differ in composition, secondary structure, and mechanism of action, allowing for synchronized targeting of multiple cellular pathways. This structural versatility, and the ability to finely control the NANPs’ sizes, shapes, composition, multivalences, and therapeutic payloads, makes this technology an attractive option for biomedical applications [5,6,7]. By extending either the 5’- or/and 3′- ends of each strand of the NANP’s composition with its unique functionality, NANPs can be formulated to precisely package different TNAs and fluorophores, targeting agents, small-molecule drugs, proteins, or other therapeutic cargoes [10,11,12]

Methods

Results

Conclusion