Lipoic Acid Derivative/PEI Composite Nanoparticles Enable Efficient mRNA Delivery via Thiol‐Mediated Cellular Uptake

Nanoparticle (NP) carriers are critical for enhancing the stability and cellular uptake of mRNA, enabling its therapeutic potential. However, conventional mRNA NP carriers enter cells via endocytosis, followed by endosome-lysosome trafficking, which leads to inefficient mRNA release into the cytoplasm. This insufficient endosomal escape has become a challenge in improving mRNA delivery efficiency for polymer and lipid NP carriers. In this study, we design a novel class of lipoic acid derivative (LA-Der) composite NPs with surface disulfide bonds that anchor onto cell membranes through disulfide exchange with cell surface thiols, bypassing endosomal degradation and directly releasing mRNA into the cytoplasm. We synthesized 25 LA-Ders with diverse chemical structures via amidation and incorporated 10 kDa polyethyleneimine (PEI) to form composite NPs for optimal mRNA loading. In vitro optimization identified three LA-Der/PEI formulations, LA-4A1, LA-5A1, and LA-6A2, as the most effective for mRNA delivery. Mechanistic studies revealed that thiol-mediated uptake is the predominant internalization pathway, facilitating the bypass of endosomal barriers. In vivo experiments confirmed high luciferase expression in the spleen and liver following intravenous injection of NPs carrying luciferase mRNA. These LA-Der/PEI composite NPs provide a promising strategy for overcoming intracellular endosomal escape barriers, advancing the clinical translation of mRNA therapeutics.