Ternary nanoparticle rigidity regulates mRNA vaccines transportation.

Various nanoparticles have been developed as safe and effective carriers for mRNA delivery, aimed at preventing degradation. Despite numerous factors considered in nanoparticle design, the influence of mechanical elasticity on their preferential transport behavior to the lymphatic system remains poorly understood. In this study, we synthesized a library of ternary nanoparticles encapsulating mRNA with tunable elastic moduli to investigate the role of nanoparticle rigidity in lymphatic transport. In vitro analyses revealed that rigid mRNA delivery systems exhibited significantly enhanced cellular internalization and transfection efficiency compared to their flexible counterparts. However, contrasting results were observed in vivo, where the soft mRNA delivery system, which demonstrated superior BSA binding ability relative to the hard system, showed enhanced lymph node accumulation and uptake by dendritic cells for protein expression. These results suggest that softer nanoparticles may be more suitable for mRNA delivery. Our findings open avenues to better understand how nanoparticle rigidity impacts mRNA delivery and immune responses.