3D-Printed Milli-Fluidic Mixing-Extrusion Platform for Continuous, High-Throughput LNP Production.

Lipid nanoparticles (LNPs) have emerged as a prominent delivery vehicle for therapeutics such as mRNA vaccines and genetic medicines. However, current manufacturing technologies struggle to balance precision, scalability, and cost-effectiveness. While microfluidic mixing offers excellent particle control, it often faces operational challenges, including channel fouling and a reliance on costly single-use chips that create bottlenecks for reproducible and scalable production of LNPs. Conversely, bulk methods lack uniformity, and conventional extrusion remains a labor-intensive batch process. Here, we report a hybrid continuous synthesis platform that integrates a reusable 3D-printed milli-fluidic mixer with inline membrane extrusion. By engineering a robust 3D internal architecture at the milli-scale, this system achieves rapid mixing while mitigating clogging risks associated with micro-channels. Our platform also offers a durable, easy-to-clean alternative that enhances process reproducibility while the integrated design enables single-pass refinement of LNPs, streamlining the production workflow to achieve high-quality, uniform LNPs at flow rates of up to 20 mL min-1. Overall, our study provides a scalable, cost-effective, and contamination-resistant pathway for industrial LNP manufacturing, overcoming the limitations of existing disposable cartridge-based systems.