Enabling Anti-inflammatory Activity through Hyaluronan-coated PLGA Nanoparticles Loaded with Carvacrol

Objective: Chronic inflammation is characterized by excessive cytokine production and macrophage infiltration, contributing to disease progression. This study aimed to enhance the therapeutic efficacy and local delivery of carvacrol (CVL), a natural PPAR-γ activator with anti-inflammatory properties, through the development of a poly(lactic-co-glycolic) acid (PLGA)-based nanoparticle delivery system with hyaluronic acid (HA)-dependent macrophage targeting. Methods: Poly(lactic-co-glycolic) acid (PLGA)-based nanoparticles encapsulating CVL (CP NPs) were prepared and coated with 1.5% w/v hyaluronic acid (HA) to form CHP NPs for CD44 receptor-mediated targeting of pro-inflammatory macrophages. Physicochemical characterization, encapsulation efficiency, and drug release profile were evaluated. Cellular uptake and cytokine modulation were assessed in lipopolysaccharide-stimulated macrophages. Results: CP NPs exhibited a size of 155 ± 3 nm and a zeta potential of -57.7 ± 1.3 mV, while HA coating yielded CHP NPs with a size of 225 ± 18 nm and a zeta potential of -25.5 ± 0.3 mV. Encapsulation efficiency and loading capacity reached 91 ± 5% and 26 ± 7%, respectively. HA coating enhanced nanoparticle internalization by 41% compared to uncoated NPs. A sustained release profile was achieved, with 50 ± 13% of CVL released over 21 days. In macrophages, CHP NPs increased anti-inflammatory cytokines IL-1ra (+ 258%), IL-4 (+ 260%), and IL-10 (+ 40%), while reducing pro-inflammatory cytokines IL-1α (-25%), IL-1β (-36%), and TNF-α (-36%) relative to untreated cells. Conclusions: HA-coated PLGA nanoparticles effectively delivered CVL, enhancing macrophage targeting and promoting an anti-inflammatory response. This platform offers a promising strategy for treating chronic inflammation-related diseases.