Continuous production of lipid nanoparticles by multiple-splitting in microfluidic devices with chaotic microfibrous channels.

Polydimethylsiloxane (PDMS) microfluidic devices with chaotic microfibrous channels were fabricated for the continuous production of lipid nanoparticles (LNPs). Electrospun poly(ε-caprolactone) (PCL) microfibrous matrices with different diameters (3.6 ± 0.3, 6.3 ± 0.4, and 12.2 ± 0.8 µm) were used as a template to develop microfibrous channels. The lipid solution (in ethanol) and water phase were introduced into the microfluidic device as the discontinuous and continuous phases, respectively. The smaller diameter of microfibrous channels and the higher flow rate of the continuous phase resulted in the smaller LNPs with a narrower size distribution. The multiple-splitting of the discontinuous phase and the microscale contact between the two phases in the microfibrous channels were the key features of the LNP production in our approach. The LNPs containing doxorubicin with different average sizes (89.7 ± 35.1 and 190.4 ± 66.4 nm) were prepared using the microfluidic devices for the potential application in tumor therapy. In vitro study revealed higher cellular uptake efficiency and cytotoxicity of the smaller LNPs, especially in the HepG2 cells. The microfluidic devices with microfibrous channels can be widely used as a continuous and high-throughput platform for the production of LNPs containing various active agents.