Advancing extracellular vesicles as drug delivery systems: a conceptual and prospective outlook on microfluidic...

Extracellular vesicles (EVs) are increasingly recognized as effective drug delivery systems because of their natural biocompatibility, ability to cross biological barriers, and inherent targeting of specific cell types. However, their clinical translation faces challenges related to scalability and the absence of reliable, efficient loading methods. Although direct studies of microfluidic EV drug loading are still limited, this paper leverages principles established in liposome engineering, nanoparticle manufacturing, and microfluidic bioprocessing to explore how microfluidics could revolutionize future EV loading strategies. Three pivotal aspects were considered: (i) precisely regulated passive loading, (ii) mechanically or electrically mediated soft active loading, and (iii) microfluidic disassembly and reassembly techniques that produce EV-mimetic vesicles. In this context, microfluidic control over flow, shear, mixing, and transport phenomena could address many limitations of current in-bulk techniques. This is thus a conceptual and prospective review: rather than providing a systematic or critical comparison of existing studies, this paper uses selected literature as a foundation to propose plausible microfluidic EV-loading strategies, discuss their mechanistic rationale, and identify the key technical constraints that must be addressed for practical and translational implementation. By exploring these emerging opportunities, the review posits that microfluidic platforms could enable the transition of EV drug loading from a heterogeneous, lab-scale process to a scalable and automated process that is compatible with good manufacturing practice (GMP) requirements, provided that appropriate materials, validation strategies, and scale-out solutions are implemented, guiding the development of the next generation of EV-based drug delivery systems.