Scalable synthesis of lipid nanoparticles for nucleic acid drug delivery using an isometric channel-size enlarging strategy

Lipid nanoparticles (LNPs) have emerged as highly effective delivery systems for nucleic acid-based therapeutics. However, the broad clinical translation of LNP-based drugs is hampered by the lack of robust and scalable synthesis techniques that can consistently produce formulations from early development to clinical application. In this work, we proposed a method to achieve scalable synthesis of LNPs by scaling inertial microfluidic mixers isometrically in three dimensions. Moreover, a theoretical predictive method, which controls the mixing time to be equal across different chips, is developed to ensure consistent particle size and size distribution of the synthesized LNPs. LNPs loaded with small interfering RNA (siRNA) were synthesized at different flow rates, exhibiting consistent physical properties, including particle size, size distribution and encapsulation efficiency. This work provides a practical approach for scalable synthesis of LNPs consistently, offering the potential to accelerate the transition of nucleic acid drug development into clinical application.