Gene Delivery with Dual pH- and GSH-Responsive Lipoamide Polymers from Controlled Polymerization of Protected Lipoic Acid

Gene delivery has great therapeutic potential, but there remain significant barriers for the effective use of this technology, including efficient transportation of the genetic payloads to the region of the cell where they are therapeutically active. Nanoparticle delivery systems have emerged as an important tool to improve the targeted delivery of nucleic acid cargo inside cells. Stimuli-responsive systems have generated particular interest for this application due to their capability to tailor the packing and effective release of nucleic acid cargo. Herein, we report dual pH- and glutathione (GSH)-responsive poly(lipoamide) (PLpAm) nanoparticles for the delivery of plasmid DNA (pDNA). PLpAm polymers were synthesized via a controlled polymerization method, followed by postpolymerization modification with pH-responsive charge-shifting pendent groups to optimize the endosomal escape capability. Our polymers efficiently complexed pDNA that encodes for an enhanced green fluorescent protein (eGFP), and the corresponding nanoparticles were shown to exhibit a dual response to pH and redox potential. A range of nanoparticles were synthesized with different N/P ratios. All nanoparticles demonstrated disassembly under acidic conditions, followed by efficient decomplexation to release pDNA upon spontaneous depolymerization of the disulfide backbone at the cytosolic GSH level. The results showed strong transfection efficiency, with the particles at the highest N/P ratio demonstrating an average transfection efficiency of 74 vs 34% for the Lipofectamine 3000 control at the same pDNA concentration. This nanoparticle library provides a promising platform for further optimization as nucleic acid delivery systems.