Sugar alcohol-modified polyester nanoparticles for gene delivery selective caveolae-mediated endocytosis

Nucleic acid-based drugs are changing the scope of emerging medicine in preventing and treating diseases. Nanoparticle systems based on lipids and polymers developed to navigate tissue-level and cellular-level barriers are now emerging as vector systems that can be translated to clinical settings. A class of polymers, poly(β-amino esters) (PBAEs) known for their chemical flexibility and biodegradability, has been explored for gene delivery. These polymers are sensitive to changes in the monomer composition affecting transfection efficiency. Hence to add functionality to these polymers, we partially substituted ligands to an identified effective polymer chemistry. We report here a new series of statistical copolymers based on PBAEs where the backbone is modified with sugar alcohols to selectively facilitate the caveolae-mediated endocytosis pathway of cellular transport. These ligands are grafted at the polymer's backbone, thereby establishing a new strategy of modification in PBAEs. We demonstrate that these polymers form nanoparticles with DNA, show effective complexation and cargo release, enter the cell via selective caveolae-mediated endocytosis, exhibit low cytotoxicity, and increase transfection in neuronal cells. Sugar alcohol-modified poly(β-amino esters) enables selective caveolae-mediated endocytosis.