A microfluidic platform for the controlled synthesis of architecturally complex liquid crystalline nanoparticles

Soft-matter nanoparticles are of great interest for their applications in biotechnology, therapeutic delivery, and in vivo imaging. Underpinning this is their biocompatibility, potential for selective targeting, attractive pharmacokinetic properties, and amenability to downstream functionalisation. Morphological diversity inherent to soft-matter particles can give rise to enhanced functionality. However, this diversity remains untapped in clinical and industrial settings, and only the simplest of particle architectures [spherical lipid vesicles and lipid/polymer nanoparticles (LNPs)] have been routinely exploited. This is partially due to a lack of appropriate methods for their synthesis. To address this, we have designed a scalable microfluidic hydrodynamic focusing (MHF) technology for the controllable, rapid, and continuous production of lyotropic liquid crystalline (LLC) nanoparticles (both cubosomes and hexosomes), colloidal dispersions of higher-order lipid assemblies with intricate internal structures of 3-D and 2-D symmetry. These particles have been proposed as the next generation of soft-matter nano-carriers, with unique fusogenic and physical properties. Crucially, unlike alternative approaches, our microfluidic method gives control over LLC size, a feature we go on to exploit in a fusogenic study with model cell membranes, where a dependency of fusion on particle diameter is evident. We believe our platform has the potential to serve as a tool for future studies involving non-lamellar soft nanoparticles, and anticipate it allowing for the rapid prototyping of LLC particles of diverse functionality, paving the way toward their eventual wide uptake at an industrial level.