Periodic asymmetric field enhances electrofusion of nanoscale lipid systems.

Electrofusion is a widely used technique for inducing membrane merging in biological systems, with applications ranging from hybrid lipid architectures to therapeutic delivery. However, the direct application of conventional electrofusion to advanced nanoscale drug carriers, such as cell membrane hybrid LNPs (cLNPs), faces challenges due to diminished dielectric response and uncontrolled particle dynamics. To address these limitations, we report a periodic asymmetric field (PAF) strategy that combines microfluidic flow with periodic electric fields to enhance nanoscale electrofusion. We systemically investigate the underlying mechanisms using computational fluid dynamics simulations, and subsequently fabricate and optimize a PAF-guided microfluidic electrofusion device (PAF-MED) for the controlled synthesis of cLNPs. These PAF-MED-synthesized cLNPs demonstrate improved fusion efficiency, augmented targeting capability, and superior therapeutic efficacy in bleomycin-induced pulmonary fibrosis murine models. This approach represents a unique advancement in the nanoscale manipulation of drug carriers towards better bio-functionality and reproducibility beyond conventional capability of electrofusion.