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. A bioorthogonal chemistry approach to address this important challenge will be described. It is based on bond-cleaving inverse electron demand Diels-Alder reaction between trans-cycloocteneand tetrazine. As illustrated in the Figure, two major goals have been achieved: 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. The in-cell activation approach has been demonstrated 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 bioorthogonal chemistry can be generalized for any siRNA of choice.

Controlled activation of RNA-based therapeutics

2019 Fall National Meeting

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