Acid-responsive polymer additives increase rna transfection from lipid nanoparticles

Abstract

Lipid nanoparticles (LNPs) are widely used for RNA delivery but are limited by inefficient RNA release following endosomal escape. Disclosed herein are hybrid polymer-lipid nanoparticles (PLNPs) incorporating acid-responsive poly(lactic acid)-block-poly(carboxybetaine) zwitterionic polymers to enhance RNA delivery efficiency. The polymers are cationic at physiological pH to enable RNA complexation but become neutral at endosomal pH, reducing RNA binding affinity and promoting release. These polymers were integrated into clinically approved LNP formulations to form PLNPs. The resulting PLNPs showed up to a 5.4-fold decrease in siRNA IC50 values and a 4-fold increase in mRNA transfection across multiple cell lines. Enhanced cytosolic RNA levels were confirmed via confocal microscopy, with uptake and endosomal escape comparable to standard LNPs. The improvement in transfection efficiency was lost when acid-inert polymers were used, confirming the role of the acid-responsive polymers. This approach provides a versatile platform to improve RNA delivery from existing LNP systems.

Dependencies are inferred from the claim text.