NanoPULSE: The first micromixer method delivering consistent lipid nanoparticle formulations seamlessly across all scales

The development of RNA-based therapies and vaccines formulated with lipid nanoparticles (LNPs) is currently hindered by the lack of a formulation technology that supports seamless scalability—from microliter-scale screening to multi-liter production. Current scale-up strategies require transitioning between incompatible mixing techniques, such as microfluidics for low-volume R&D production and T-mixing or impingement jet mixing (IJM) at large-scale. These transitions introduce variability in critical LNP quality attributes, including size, polydispersity index (PDI), encapsulation efficiency (EE%), and morphology. Such inconsistencies directly impact the efficacy, toxicity and biodistribution of the final drug product hence leading to prolonged development timelines, increased costs, and a high risk of failure during tech transfer. We present NanoPULSE, a patented micromixing technology designed to bridge this scalability gap and enable the consistent formulation of identical nanoparticles and RNA-LNPs at any production scale. The system uses high-frequency valves to sequentially inject aqueous and organic phases into an optimized T-junction, enhancing mixing efficiency based on the Taylor-Aris dispersion principle. This method ensures robust and uniform mixing for LNP formulation independent of volume. First, numerical Lagrangian simulations were conducted to evaluate the impact of mixing parameters on nanoparticle characteristics and to optimize the channel geometry. These simulations led to the development of a novel metric for quantifying NanoPULSE’s mixing efficiency. Experimental validation using multi-angle dynamic light scattering (MADLS) demonstrated that both empty and RNA-loaded LNPs maintain consistent sizes and low PDI values (below 0.2) across a broad range of production volumes, from 500 µL to 4 L. Encapsulation efficiency, yield, and structural morphology were assessed and showed to be consistent and comparable to, or better than, state-of-the-art microfluidic systems. NanoPULSE was shown to enable fine control over LNP size by adjusting the injection frequency, all while using a single formulation recipe. The close alignment between experimental results and simulation predictions reinforces the connection between mixing dynamics and nanoparticle properties. Together, these findings establish NanoPULSE as a robust, scalable, and reproducible platform for RNA-LNP production, with direct implications for accelerating RNA drug development and facilitating industrial translation.