Dual Stimuli‐Responsive Polylipoamide Nanoparticles as a Versatile Platform for Efficient pDNA and mRNA Delivery

Stimuli‐responsive nanoparticles have generated significant interest in gene delivery owing to their ability to provide more specific cargo release at target sites. Dual pH‐ and reduction‐responsive polylipoamide (PLpAm) nanoparticles have demonstrated great promise in plasmid DNA (pDNA) delivery. Herein, the versatility of PLpAm nanoparticles for efficient delivery of both pDNA and mRNA is reported. A series of PLpAm polymers modified with pH‐responsive moieties that can complex pDNA was designed by varying complexing moieties, including dimethylamine, guanidine, imidazole, imidazolium, and diethylenetriamine (DET). These nanoparticles demonstrated distinct differences in material properties, particularly in stimuli‐responsive behavior, and in vitro efficacy. DET‐functionalized nanoparticles (BPD PNPs) showed the highest biocompatibility and significantly higher transfection efficiency (>95%) compared to DLin‐MC3‐DMA (MC3) lipid nanoparticles, which exhibited ∼30% transfection efficiency and moderate protein expression in pDNA delivery. To extend PLpAm nanoparticles for mRNA delivery, BPD PNPs were further formulated with mRNA and demonstrated potential in mRNA delivery achieving ∼80% transfection efficiency. Moreover, Cy5‐labelled BPD PNPs were detectable in liver, lungs, and spleen following intravenous administration, but luciferase expression was restricted to lungs and spleen, demonstrating selective mRNA translation and a favorable safety profile. These findings highlight the versatility of dual stimuli‐responsive PLpAm nanoparticles for efficient gene delivery.