Issue 8, 2017

Controlled in-cell activation of RNA therapeutics using bond-cleaving bio-orthogonal chemistry

Abstract

Temporal control of siRNA activation is a major challenge for RNAi-based therapeutics. The majority of the reported siRNA delivery systems rely on environmental factors, such as differences in extracellular and intracellular redox potential, ATP concentration, or pH to activate an siRNA payload. However dynamic endogenous environments are far too complex to rely on for controllable siRNA release and can result in premature siRNA activation prior to reaching the intended biological target. In addition, there are uncertainties about timing, degree and rate of the siRNA activation with spontaneous release approaches. Herein we describe a bio-orthogonal chemistry approach to address this important challenge. With our approach we were able achieve two major goals: complete siRNA inactivation upon immobilization of the payload on the surface of iron oxide nanoparticles and controlled in-cell activation with the addition of a small non-toxic chemical trigger after sufficient cellular uptake of the nanoparticles was confirmed. We have demonstrated our in-cell activation approach using two siRNAs against green fluorescent protein (GFP) and cyclin dependent kinase 8 (CDK8) in GFP expressing MDA-MB-231 cell line. We anticipate that this methodology will potentially advance the clinical translation of RNAi-based therapeutics, as the described bio-orthogonal chemistry can be generalized for any siRNA of choice.

Graphical abstract: Controlled in-cell activation of RNA therapeutics using bond-cleaving bio-orthogonal chemistry

Supplementary files

Article information

Article type
Edge Article
Submitted
28 Mar 2017
Accepted
13 Jun 2017
First published
14 Jun 2017
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2017,8, 5705-5712

Controlled in-cell activation of RNA therapeutics using bond-cleaving bio-orthogonal chemistry

I. Khan, Leah M. Seebald, N. M. Robertson, M. V. Yigit and M. Royzen, Chem. Sci., 2017, 8, 5705 DOI: 10.1039/C7SC01380A

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements