Despite the success of mRNA lipid nanoparticle therapeutics, bottlenecks persist in limited cellular expression and uncontrolled encapsulation and release kinetics. Here we introduce a microfluidics-based method, MIMAC (microfluidic integrated mRNA amplification circuit), that restructures preformed lipid nanoparticles by inserting a metabolic enhancing RNA to an internal peripheral compartment while relocating the therapeutic RNA towards the core. Rapid shear-mediated reorganization generates a defined peripheral-to-core RNA arrangement that enables sequential cytosolic availability: early release of the metabolic RNA elevates ATP levels up to 4.2-fold and enhances following translation of the therapeutic RNA. The approach is compatible with multiple nucleic acid types—including linear, circular and self-amplifying RNA and plasmid DNA—and with varied lipid formulations. In mice, the structured lipid nanoparticles improve a human papillomavirus cancer vaccine, suppressing tumour growth by 89.2% and increasing survival. Applied to SARS-CoV-2 vaccines, our method boosts antibody titres by 62.3- to 174.8-fold while maintaining potency at one-tenth the dose. A benchtop device produces 200 doses per hour, supporting scalable use.

Nature Biomedical Engineering, 2026, https://www.nature.com/articles/s41551-026-01796-3