Enhancing mRNA-LNP Production with Optimized Microfluidic Baffles

Efficient delivery of RNA therapeutics hinges on the quality and consistency of lipid nanoparticles (LNPs) used to encapsulate mRNA. Traditional LNP synthesis methods, like pipette or vortex mixing, offer limited control and reproducibility, making it difficult to scale up for clinical use. While microfluidics offers better precision and tunability, optimizing microchannel design for effective mixing without causing excessive pressure buildup remains a key challenge.

The authors of this study tackled this issue by engineering microfluidic chips with tilted rectangular baffle structures to improve mixing efficiency and control pressure drop during mRNA-LNP synthesis. By carefully tuning the angle and length of the baffles, they aimed to boost the uniformity and transfection performance of LNPs, while keeping the system scalable for larger production volumes.

“The inherent instability of RNA and its delivery challenges necessitate the use of lipid-based nanoparticles as crucial transport vehicles. This research focuses on the design, simulation, and optimization of various microfluidic channel configurations for fabricating poly(dimethylsiloxane) (PDMS) microfluidic chips, aimed at producing lipid nanoparticles (LNPs) encapsulating green fluorescent protein mRNA (GFP mRNA).“, the authors explained.

The research team used computational fluid dynamics (CFD) to simulate and compare various designs for the microfluidic devices. They focused on flow-focusing geometries combined with tilted baffles ranging from 40° to 90° in angle and 100–175 μm in length. Pressure drop and mixing index were evaluated across flow rates from 300 to 1200 μL/min.

The microfluidic fabrication was conducted using PDMS and standard lithographic techniques. The best-performing configuration, a 70° baffle angle and 150 μm length, was used to produce LNPs encapsulating GFP mRNA. The chips enabled continuous, controllable production of LNPs by mixing aqueous mRNA solutions with lipid-containing ethanol streams. 

Simulations showed that baffles at 70–90° angles provided high mixing efficiency, but higher angles incurred greater pressure drops. Increasing baffle length also improved mixing but at the cost of higher pressure. The 70°/150 μm configuration struck the best balance. Experimental results aligned with the simulations: this microfluidic design produced LNPs under 100 nm in size with low polydispersity (PDI < 0.2). When GFP mRNA was loaded, an N/P ratio of 5.6 yielded the highest transfection efficiency in HEK cells with minimal cytotoxicity.

Simulations showed that baffles at 70–90° angles provided high mixing efficiency, but higher angles incurred greater pressure drops. Increasing baffle length also improved mixing but at the cost of higher pressure. The 70°/150 μm configuration struck the best balance. Experimental results aligned with the simulations: this microfluidic design produced LNPs under 100 nm in size with low polydispersity (PDI < 0.2). When GFP mRNA was loaded, an N/P ratio of 5.6 yielded the highest transfection efficiency in HEK cells with minimal cytotoxicity.

This study demonstrates that subtle geometric changes in microfluidic baffle design can significantly impact LNP formulation outcomes. By selecting the optimal baffle configuration, the authors achieved high-quality mRNA-LNPs suitable for gene delivery, while maintaining scalability. This work sets the stage for rapid screening and clinical translation of RNA therapeutics using microfluidic platforms.

“Having identified an optimal structure for LNP preparation, the next step is to develop a systematic microfluidic platform using plastic microfluidic chips. This platform will enable faster, more efficient, and highly reproducible LNP production, significantly accelerating the formulation process and facilitating the rapid clinical application of LNPs. It will also effectively tackle the challenge of quickly screening suitable formulations for clinical use.
“, the authors concluded

Figures are reproduced from Mingzhi Yu, Dongsheng Liu, Pranay Shah, Bei Qiu, Allen Mathew, Liang Yao, Tianyu Guan, Hengji Cong, and Nan Zhang ACS Biomaterials Science & Engineering 2025 11 (6), 3762-3772 DOI: 10.1021/acsbiomaterials.4c02373 under Creative Commons Attribution 4.0 International License.

Read the original article: Optimizing Microfluidic Channel Design with Tilted Rectangular Baffles for Enhanced mRNA-Lipid Nanoparticle

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