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

ABSTRACT 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.