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Inflammation, a crucial defense mechanism, must be rigorously regulated to prevent the onset of chronic inflammation and subsequent tissue damage. Specialized pro resolving mediators (SPMs) such as lipoxin A4 (LXA4) have demonstrated their ability to facilitate the resolution of inflammation by orchestrating a transition of M1 pro-inflammatory macrophages towards an anti-inflammatory M2 phenotype. However, the hydrophobic and chemically labile nature of LXA4 necessitates the development of a delivery system capable of preserving its integrity for clinical applications. In this study, two types of emulsion were formulated using different homogenization processes:mechanical overhead stirrer (MEB for blank Emulsion and MELX for LXA4 loaded-Emulsion) or Luer-lock syringes (SEB for blank Emulsion and SELX for LXA4 loaded-Emulsion)). Following characterization, including size and droplet morphology assessment by microscopy, the encapsulation efficiency (EE) was determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). To exert control over LXA4 release, these emulsions were embedded within silanized hyaluronic acid hydrogels. A comprehensive evaluation, encompassing gel time, swelling, and degradation profiles under acidic, basic, and neutral conditions, preceded the assessment of LXA4 cumulative release using LC-MS/MS. Physicochemical results indicate that H-MELX (Mechanical overhead stirrer LXA4 Emulsion loaded-Hydrogel) exhibits superior efficiency over H-SELX (Luer-lock syringes LXA4 Emulsion loaded-Hydrogel). While both formulations stimulated pro-inflammatory cytokine secretion and promoted a pro-inflammatory macrophage phenotype, LXA4 emulsion-loaded hydrogels displayed a diminished pro-inflammatory activity compared to blank emulsion-loaded hydrogels. These findings highlight the biological efficacy of LXA4 within both systems, with H-SELX outperforming H-MELX in terms of efficiency. To the best of our knowledge, this is the first successful demonstration of the biological efficacy of LXA4 emulsion-loaded hydrogel systems on macrophage polarization. These versatile H-MELX and H-SELX formulations can be customized to enhance their biological activity making them promising tools to promote the resolution of inflammation in diverse clinical applications. [ABSTRACT FROM AUTHOR]