Synthesis and bioactivity of a novel surfactin-based lipopeptide for mRNA delivery.

The effective delivery of messenger ribonucleic acid (mRNA) to specific cell types and target tissues poses a significant challenge in nonviral therapeutic strategies. Lipid-based nanoparticles (LNPs) have emerged as a leading carrier system for delivering mRNA, particularly for infectious diseases, such as COVID-19. This study aimed to describe the synthesis of a novel lipopeptide based on surfactin, a naturally occurring surfactant. Additionally, a series of novel LNPs were rationally designed, based on the modified surfactin, OleSurf, and were formulated and optimized. The physicochemical properties, morphologies, and stabilities of the particles were evaluated. All formulations containing OleSurf produced particles with a diameter <80 nm and an encapsulation efficiency >95%. OleSurf LNPs demonstrated excellent transfection efficiency and luciferase expression with no cytotoxicity, compared to lipofectamine 2000, a known transfection reagent, and were comparable to the DLin-MC3-DMA lipid. OleSurf-based LNPs behaved as efficient mRNA carriers and showed enhanced mRNA-binding capabilities, associated with facilitated intracellular release, endosomal escape, and protection from endonuclease degradation. In addition, OleSurf-LNPs showed a higher mRNA delivery efficiency, a more advantageous biodistribution pattern, and an improved safety profile in vivo . Overall, the novel OleSurf LNPs presented an optimal delivery platform for mRNA therapeutics.