Microfluidic-assembled curcumin ionizable lipid nanoparticles enhance aqueous delivery and antibiofilm activity against Staphylococcus aureus.

Antimicrobial resistance and biofilm-associated infections demand novel therapeutic strategies. Curcumin is a natural polyphenol with broad-spectrum antimicrobial activity; however, its clinical utility is fundamentally constrained by negligible aqueous solubility and limited biofilm penetration. Here, we used microfluidic assembly to prepare curcumin-loaded ionizable lipid nanoparticles (Cur@LNP) with three clinically established ionizable lipids (SM-102, MC-3, and ALC-0315). The resulting formulations were uniform, with hydrodynamic diameters of approximately 90 nm and polydispersity indices near 0.1. Relative to free curcumin in DMSO, Cur@LNP lowered the minimum inhibitory concentration (MIC) 8-fold and the minimum bactericidal concentration (MBC) 16-fold against planktonic Staphylococcus aureus, and markedly reduced viable biofilm-resident cells at matched concentrations. Scanning electron microscopy showed that Cur@LNP treatment remodeled mature biofilms into irregular, debris-rich aggregates with reduced extracellular matrix coverage. Notably, antimicrobial performance was indistinguishable across the three structurally distinct ionizable lipids at every concentration tested. Within this in vitro, single-strain system, the antibiofilm effect is therefore dominated by the cargo (curcumin) rather than by ionizable-lipid chemistry, and it is most likely attributed to enhanced aqueous solubilization of curcumin rather than to engagement of the lipid headgroup with the biofilm matrix. These results position microfluidic-assembled ionizable LNPs as a reproducible, scalable solubilization platform for poorly water-soluble natural antimicrobials.