Macrophages possess an innate ability to scavenge heterogenous objects from the systemic circulation and to regulate inflammatory diseases in various organs via cytokine production. That makes them attractive targets for nanomedicine-based therapeutic approaches to inflammatory diseases. In the present study, we have prepared several different poly(lactic-co-glycolic acid) (PLGA) polymer nanospheres for macrophage-targeted drug delivery using both nanoprecipitation and emulsification solvent evaporation methods. Two experimental linear PLGA polymers with relatively low molar weight, one experimental branched PLGA with unique star-like molecular architecture, and a commercially available PLGA, were used for nanosphere formulation and compared to their macrophage uptake capacity. The nanosphere formulations labelled with loaded fluorescent dye Rhodamine B were further tested in mouse bone marrow-derived macrophages and in hepatocyte cell lines AML-12, HepG2. We found that nanospheres larger than 100 nm prepared using nanoprecipitation significantly enhanced distribution of fluorescent dye selectively into macrophages. No effects of nanospheres on cellular viability were observed. Additionally, no significant proinflammatory effect after macrophage exposure to nanospheres was detected as assessed by a determination of proinflammatory cytokines Il-1β and Tnfα mRNA. All experimental PLGA nanoformulations surpassed the nanospheres obtained with the commercially available polymer taken as a control in their capacity as macrophage-specific carriers.

Glucocorticoids are potent anti‐inflammatory drugs, although their use is associated with severe side effects. Loading glucocorticoids into suitable nanocarriers can significantly reduce these undesirable effects. Macrophages play a crucial role in inflammation, making them strategic targets for glucocorticoid‐loaded nanocarriers. The main objective of this study is to develop a glucocorticoid‐loaded PLGA nanocarrier specifically targeting liver macrophages, thereby enabling the localized release of glucocorticoids at the site of inflammation. Dexamethasone acetate (DA)‐loaded PLGA nanospheres designed for passive macrophage targeting are synthesized using the nanoprecipitation method. Two types of PLGA NSs in the size range of 100–300 nm are prepared, achieving a DA‐loading efficiency of 19 %. Sustained DA release from nanospheres over 3 days is demonstrated. Flow cytometry analysis using murine bone marrow‐derived macrophages demonstrates the efficient internalization of fluorescent dye‐labeled PLGA nanospheres, particularly into pro‐inflammatory macrophages. Significant down‐regulation in pro‐inflammatory cytokine genes mRNA is observed without apparent cytotoxicity after treatment with DA‐loaded PLGA nanospheres. Subsequent experiments in mice confirm liver macrophage‐specific nanospheres accumulation following intravenous administration using in vivo imaging, flow cytometry, and fluorescence microscopy. Taken together, the data show that the DA‐loaded PLGA nanospheres are a promising drug‐delivery system for the treatment of inflammatory liver diseases.

Obeticholic acid (OCA), a potent farnesoid X receptor agonist, is approved for the treatment of primary biliary cholangitis and is being investigated for broader applications in hepatic inflammation. However, systemic exposure following oral administration often leads to off-target effects. In this study, we developed poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) to improve the therapeutic profile of OCA through targeted liver delivery. The NPs were prepared using a rapid, scalable, and pH-responsive nanoprecipitation method that enabled precise control of particle size and encapsulation efficiency. Two PLGA compositions (50:50 and 75:25 lactic-to-glycolic acid ratios) were used, yielding NPs ranging from 35 to 193 nm with encapsulation efficiency decreasing from 89% at pH 2.5 to 15% at pH 10.0. In vitro release studies demonstrated a pH-responsive release profile, with significantly slower OCA release under acidic conditions. OCA-loaded NPs showed excellent biocompatibility in primary murine macrophages and significantly reduced the cytotoxicity associated with free OCA. Moreover, they retained OCA’s anti-inflammatory activity in LPS-stimulated THP-1 macrophages, reducing IL-6 expression and inducing SHP upregulation. Biodistribution confirmed preferential liver accumulation of DiR-labeled OCA-loaded NPs following intravenous administration. Collectively, these results demonstrate that pH-tunable PLGA NPs represent a promising platform for targeted hepatic delivery and controlled release of OCA.