Microfluidic ultrasonic cavitation enables versatile and scalable synthesis of monodisperse nanoparticles for biomedical application

Abstract

Controllable and scalable synthesis of biomedical organic nanoparticles (NPs) with tailored properties is critical for their clinical translation. However, the existing microfluidics-based synthesis is challenged by clogging and limited throughput, while the traditional ultrasound-assisted synthesis suffers from inhomogeneous cavitation activity, leading to wide particle size distribution. Herein, a series of biomedical organic NPs were successfully synthesized in a controlled, clog-free and scalable manner via a versatile microfluidic ultrasonic cavitation (MUC) approach. First, the effects of microchannel dimension and operating conditions on ultrasonic cavitation behavior and mixing performance was systematically studied. Cavitation pattern maps were developed for different operating conditions. By adjusting microchannel dimension and operating parameters, rapid mixing on a millisecond scale can be accomplished across an extensive range of conditions, including flow rates between 4 and 24 mL/min and flow rate ratios from 5:1 to 1:1. Then, the MUC approach was utilized to synthesize polymeric NPs, lipopolymeric NPs and lipid NPs encapsulating mRNA (mRNA-LNP). Compared to traditional microfluidics and ultrasound-based methods, NPs synthesized by MUC approach showed smaller sizes and more uniform distributions. The ability of MUC approach for clog-free and scalable production was demonstrated by the continuous synthesis of lipopolymeric NPs at a throughput of 1.6 g/h with desired properties. The successful synthesis of soft and fragile mRNA-LNPs has been accomplished by tailoring the cavitation pattern of MUC approach. The resultant mRNA-LNPs showed a mRNA encapsulation rate as high as 98.3%, over 99% transfection efficiency of cell with 0.5 μg dosage, and robust luciferase expression with 10 μg dosage at the injection site of BALB/c mice 24 h after injection.