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DNA-inspired nanomaterials for enhanced endosomal escape
Thursday, 2021/05/13 | 07:22:29

Jinhyung Lee et al. - PNAS May 11, 2021,  118 (19) e2104511118


To realize RNA interference (RNAi) therapeutics, it is necessary to deliver therapeutic RNAs (such as small interfering RNA or siRNA) into cell cytoplasm. A major challenge of RNAi therapeutics is the endosomal entrapment of the delivered siRNA. In this study, we developed a family of delivery vehicles called Janus base nanopieces (NPs). They are rod-shaped nanoparticles formed by bundles of Janus base nanotubes (JBNTs) with RNA cargoes incorporated inside via charge interactions. JBNTs are formed by noncovalent interactions of small molecules consisting of a base component mimicking DNA bases and an amino acid side chain. NPs presented many advantages over conventional delivery materials. NPs efficiently entered cells via macropinocytosis similar to lipid nanoparticles while presenting much better endosomal escape ability than lipid nanoparticles; NPs escaped from endosomes via a “proton sponge” effect similar to cationic polymers while presenting significant lower cytotoxicity compared to polymers and lipids due to their noncovalent structures and DNA-mimicking chemistry. In a proof-of-concept experiment, we have shown that NPs are promising candidates for antiviral delivery applications, which may be used for conditions such as COVID-19 in the future.


See: https://www.pnas.org/content/118/19/e2104511118

Figure: NP assembly and endocytosis. (A) Schematic drawing of NPs’ delivery. (B) The ζ-potential analysis. (C) UV-Vis analysis. (D) TEM characterization of the NPs. (E) Gel retardation assay. (F) CLSM z-stack images of siRNA-AF488 (green) delivered by the NPs; cell nuclei stained with DAPI (blue); cell skeleton stained with rhodamine phalloidin (red). (G) Inhibition of NP uptake. (H) Quantitative analysis of NP uptake. The values are mean ± SEM (n ≥ 10). *P < 0.05, **P < 0.01, and ***P < 0.001 compared to control.

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