Bait-and-Switch Supramolecular Strategy To Generate Noncationic RNA–Polymer Complexes for RNA Delivery

RNA interference (RNAi) requires the intracellular delivery of RNA molecules to initiate the neutralization of targeted mRNA molecules, inhibiting the expression or translation of the targeted gene. Current polymers and lipids that are used to deliver RNA molecules are generally required to be positively charged, to achieve complexation with RNA and the cellular internalization. However, positive surface charge has been implicated as the reason for toxicity in many of these systems. Herein, we report a novel strategy to generate noncationic RNA–polymer complexes for RNA delivery with low cytotoxicity. We use an in situ electrostatic complexation using a methylated pyridinium group, which is simultaneously removed during the RNA binding step. The resultant complexes demonstrate successful knockdown in preimplantation mammalian embryos, thus providing a new approach for nucleic acid delivery.