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

Abstract

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.

Noncationic Material Design for Nucleic Acid Delivery

“…Very recently, Thayumanavan and co‐workers designed a two‐step approach to formulate noncationic RNA–polymer complexes for RNA delivery ( Figure ). [ 44 ] The design starts with the complexation between cationic polymers and RNA to form RNA–polymer polyelectrolytes. The positive charge was contributed by the N ‐methylated pyridyl disulfide derivative on the polymer side chains.…”

Disulfide‐Containing Macromolecules for Therapeutic Delivery

“…Apart from the disulfide moiety, the pyridine moiety within PDS provides another site for the functionalization of PDS‐containing polymers. In a recent report, N ‐methylation reaction was achieved on the PDS side chains of a random copolymer, generating a positively charged copolymer (Figure ) . These cationic polymers were subsequently complexed with RNA through electrostatic interaction.…”

Reactive Precursor Particles as Synthetic Platform for the Generation of Functional Nanoparticles, Nanogels, and Microgels

“…Furthermore, the Thayumanavan group applied the thiol–disulfide exchange reaction for postfunctionalization of noncationic RNA–polymer complexes . Methylated pyridyl disulfide groups among the polymeric scaffold were the key of this synthetic strategy.…”

“…Methylated pyridyl disulfide groups among the polymeric scaffold were the key of this synthetic strategy. On the one hand, the cationic nature of the functional groups initiated the complexation of the RNA, while on the other hand these moieties could undergo thiol–disulfide exchange reaction for crosslinking . In a follow up study, remaining pyridyl disulfide groups after crosslinking were used to PEGylate the complex using a thiol‐terminated PEG …”