Structurally defined mRNA-LNPs formulation using automated inline monitoring and hydrodynamically enhanced system

The clinical translation efficacy of mRNA-loaded lipid nanoparticles (LNPs) critically depends on their structural and compositional uniformity, but conventional batch-to-batch processing methods struggle to meet this challenge. To address this, we developed a closed-loop robotic platform integrating a computational fluid dynamics (CFD)-optimized microfluidic mixer with asymmetric herringbone grooves and an inline organic electrochemical transistor (OECT) for real-time impedance monitoring. The mixer achieved >99.99% mixing efficiency at flow rates ≥ 10 mL/min with minimal energy dissipation, and this accomplishment enabled rapid synthesis of monodisperse LNPs (polydispersity index [PDI] < 0.1 and encapsulation efficiency > 95%). Coupled with real-time OECT-based feedback for detecting compositional changes, the system produced LNPs with superior structural homogeneity, a higher mRNA payload, and a lower empty particle ratio—which are key clinical side effects of mRNA-LNPs—compared with a leading commercial product. In vivo results confirmed enhanced transfection efficiency, thus directly linking optimized hydrodynamic control to improved functional performance and underscoring the platform's potential for scalable, high-quality LNPs production.