doi:10.1039/d5nh00782hengEsteban-Pérez, NataliaDel Sol-Fernández, SuselMartín-Rapún, RafaelMartínez de la Fuente, JesúsControlled release of glucocorticoid via PLGA nanoparticles for modulating macrophage polarization in inflammation situationsART-2026-148745Glucocorticoids 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.2026http://zaguan.unizar.es/record/17017210.1039/d5nh00782hhttp://zaguan.unizar.es/record/170172oai:zaguan.unizar.es:170172info:eu-repo/grantAgreement/ES/DGA/E15-20Rinfo:eu-repo/grantAgreement/EC/HORIZON EUROPE/101064735/EU/Tunning the force for remote magnetomechanical gating of Piezo1 channels/MAGPIEZinfo:eu-repo/grantAgreement/ES/ISCIII/CB16-01/00263info:eu-repo/grantAgreement/ES/MICINN/CEX2023-001286-Sinfo:eu-repo/grantAgreement/ES/MICINN/PID2020-118485RB-I00info:eu-repo/grantAgreement/ES/MICINN/PID2022-141276OB-I00Nanoscale Horizons (2026), [10 pp.]by-nchttps://creativecommons.org/licenses/by-nc/4.0/deed.esinfo:eu-repo/semantics/openAccess