Controlled release of glucocorticoid via PLGA nanoparticles for modulating macrophage polarization in inflammation situations

Glucocorticoids are among the most widely used anti-inflammatory and immunosuppressive drugs. However, their prolonged administration is associated with a wide range of adverse side effects including long-lasting immunosuppression. In this study, we aimed to encapsulate two commonly used glucocorticoids with different potency and duration, hydrocortisone and dexamethasone, into poly(lactic-co-glycolic acid) (PLGA) nanoparticles with the goal to modulate inflammatory gene expression in a delivery-dependent manner. We evaluated their anti-inflammatory properties in two in vitro models varying the timing of treatment administration based on lipopolysaccharide M1-polarized macrophages, key effectors of the innate immune system. Our results demonstrated that, for both strategies, drug-loaded nanoparticles significantly reduced the expression of interleukin-6, a pro-inflammatory cytokine, compared to the free drugs. However, in one of the strategies, while free drugs induced upregulation of interleukin-10, a key anti-inflammatory cytokine, no such effect was observed with the nanoparticle-based formulations. Overall, these results demonstrate that PLGA nanoparticles enable sustained glucocorticoid delivery and modulate inflammatory gene expression in activated macrophages in a delivery- and timing-dependent manner, providing comparative insight into how glucocorticoid delivery via PLGA nanoparticles shapes inflammatory gene regulation depending on treatment timing and highlighting the importance of in vitro model design.