The delivery of messenger RNA (mRNA) to cells and tissues has the potential to fundamentally impact the detection and treatment of disease in areas of protein replacement therapy, vaccination, and genome editing by inducing the transient expression of exogenous proteins. However, the difficulty in delivering mRNA transcripts to cultured cells and in vivo targets requires new approaches to expand its clinical adoption. Here we report a new class of biodegradable delivery materials: charge-altering releasable transporters (CARTs), which are easily synthesized by the organocatalytic ring-opening polymerization of cyclic monomers. These CARTs are structurally unique and operate through an unprecedented mechanism, serving initially as oligo(α-amino ester) cations that complex, protect, and deliver mRNA, and then change physical properties through a degradative, charge-neutralizing intramolecular rearrangement, leading to intracellular release of functional mRNA and highly efficient protein translation. We demonstrate the utility of these materials for inducing mRNA expression in a wide range of cultured cell lines with &gt;95% transfection efficiencies, and at high levels in animals through multiple routes of administration. We further show that the increased efficacy of these materials relative to non-rearranging oligomers is a direct consequence of their controlled immolation to neutral small molecules. The synthetic accessibility, and superior in vitro and in vivo efficacy of these CARTs should enable their broad adoption in numerous research and therapeutic applications.

Charge-Altering Releasable Transporters (CARTs) for the delivery and release of messenger RNA in living animals

253rd National Meeting (2017)

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