Selective Blood Cell Hitchhiking in Whole Blood With Ionic Liquid-Coated PLGA Nanoparticles to Redirect...

Nanoparticles (NPs) are great for systemic drug delivery because they can encapsulate diverse therapeutics, protect cargo from degradation, and enable controlled release profiles. Their performance, however, strongly depends on the ability to circulate stably and reach target tissues after administration. Intravenously delivered NPs typically experience rapid opsonization and clearance, resulting in less than 5% delivery to intended tissues. Cellular hitchhiking, in which NPs adsorb onto endogenous blood cells, offers a route to extend circulation and redirect biodistribution, yet existing approaches provide limited control over cell selectivity. This work presents a modular platform in which choline carboxylate ionic liquids (ILs) coat poly(lactic-co-glycolic acid) (PLGA) NPs to engineer selective interactions with defined blood cell populations and promote in situ hitchhiking to lymphocytes, monocytes, granulocytes, platelets, and red blood cells (RBCs). The resulting IL-PLGA NPs display low cytotoxicity, markedly reduced plasma residence, and significantly prolonged circulation in healthy mice after intravenous injection. Distinct IL chemistries produce unique organ-targeting profiles, enabling biodistribution patterns not accessible with unmodified PLGA NPs. The findings demonstrate a tunable IL-nanoparticle interface capable of directing blood cell-specific hitchhiking and establish a generalizable strategy for improving systemic drug delivery through engineered bio-nano interactions.