Microfluidic approaches for producing lipid-based nanoparticles for drug delivery applications

The importance of drug delivery for disease treatment is supported by a vast literature and increasing ongoing clinical studies. Several categories of nano-based drug delivery systems have been considered in recent years, among which lipid-based nanomedicines, both artificial and cell-derived, remain the most approved. The best artificial systems in terms of biocompatibility and low toxicity are liposomes, as they are composed of phospholipids and cholesterol, the main components of cell membranes. Extracellular vesicles-biological nanoparticles released from cells-while resembling liposomes in size, shape, and structure, have a more complex composition with up to hundreds of different types of lipids, proteins, and carbohydrates in their membranes, as well as an internal cargo. Although nanoparticle technologies have revolutionized drug delivery by enabling passive and active targeting, increased stability, improved solubilization capacity, and reduced dose and adverse effects, the clinical translation remains challenging due to manufacturing limitations such as laborious and time-consuming procedures and high batch-to-batch variability. A sea change occurred when microfluidic strategies were employed, offering advantages in terms of precise particle handling, simplified workflows, higher sensitivity and specificity, and good reproducibility and stability over bulk methods. This review examines scientific advances in the microfluidics-mediated production of lipid-based nanoparticles for therapeutic applications. We will discuss the preparation of liposomes using both hydrodynamic focusing of microfluidic flow and mixing by herringbone and staggered baffle micromixers. Then, an overview on microfluidic approaches for producing extracellular vesicles and extracellular vesicles-mimetics for therapeutic applications will describe microfluidic extrusion, surface engineering, sonication, electroporation, nanoporation, and mixing. Finally, we will outline the challenges, opportunities, and future directions of microfluidic investigation of lipid-based nanoparticles in the clinic.