Gravity-driven microfluidic synthesis of lipid nanoparticles via vibrating sharp-tip mixing.

Lipid nanoparticles (LNPs) are widely used in nanomedicine, yet their energy-efficient manufacture with precise control over particle uniformity remains challenging. Here we report a gravity-driven microfluidic platform that integrates acoustically actuated sharp-tip mixing to enable high-throughput LNPs synthesis without the need for active pumps. By optimizing microchannel geometry, actuation conditions, and the spatial positioning of the mixing vortex, we achieve stable gravity-driven flow and complete mixing at total flow rates (TFRs) of up to 5 ml min-1. The optimized system produces LNPs with tunable sizes below 60 nm, polydispersity <0.3, and high production yields. We further show that nanoparticle uniformity is governed not only by mixing strength but also by where mixing and nucleation occur within the microchannel. These findings establish gravity-driven sharp-tip microfluidics as a scalable and energy-efficient strategy for controlled nanoparticle manufacturing, offering a practical route toward greener nanomedicine production.