Scalable Microfluidic Manufacturing of Theranostic Liposomes: Batch Consistency and GMP-Ready Process Design

Abstract

Theranostic liposomes carry a drug and an imaging agent in the same particle, so that treatment and the means of watching it arrive together. Few have reached patients, and the obstacle is more often manufacturing than biology. Conventional bulk routes — thin-film hydration, ethanol injection, high-pressure homogenisation — rely on turbulent mixing in which nucleation conditions vary from one region of the vessel to the next. The products are correspondingly uneven: diameters of roughly 120–200 nm, polydispersity above 0.25, modest entrapment of hydrophilic contrast agents, and a drift between lots that regulators are unlikely to overlook. This review asks how far microfluidic continuous-flow manufacturing closes that gap. Drawing on twelve verified sources published between 2013 and 2026, we compare hydrodynamic flow focusing, staggered herringbone, Dean-flow and active micromixers, relating their operating variables — chiefly total flow rate and flow rate ratio — to the attributes that matter for release. A consistent picture emerges. Millisecond laminar mixing yielded vesicles of about 30–120 nm with polydispersity below 0.10–0.20 and encapsulation of roughly 70–95%, across payloads as different as a hydrogel core holding iopamidol and doxorubicin, indocyanine green J-aggregates stabilised within a rigid bilayer, cRGD-targeted gadolinium liposomes, and exosome-wrapped cubosomes assembled by low-shear fusion. Replicating channels rather than accelerating one raised throughput more than a hundredfold without altering particle quality. What remains unsettled is the translational half: anti-PEG immunity, protein-corona masking of ligands, uneven EPR-dependent delivery, and the regulatory status of drug–imaging combinations. We close with a Quality-by-Design framework linking device choice to process analytics and release criteria.