Stability, Efficacy, and Immunomodulatory Impact of Nanoemulsion-Encapsulated Lipoxin A4 in the context of pulpal inflammation.

Lipoxin A4 (LXA4) is a specialized pro-resolving mediator with potential to modulate dental pulp inflammation. However, its therapeutic use is limited by instability and rapid degradation. This study aimed to develop and evaluate LXA4-loaded nanoemulsions (NELX) as a delivery system to promote inflammation resolution both in vitro and in vivo. NELX were formulated with LXA4 and characterized by dynamic light scattering, tunable resistive pulse sensing, scanning transmission electron microscopy, and liquid chromatography-tandem mass spectrometry. Encapsulation efficiency, stability, and drug payload were determined. In vitro, THP-1-derived macrophages (M0, M1, M2) were exposed to NELX, and metabolic activity, cytokine expression, and secretion were assessed. In vivo efficacy was investigated in a murine air pouch model and a rat molar pulpitis model. Histologic and immunohistochemical analyses (hematoxylin and eosin, CD68, CD163) were performed. NELX achieved complete encapsulation (100%) of 20 μM LXA4 by day 3 and remained stable for 45 days at 4°C. In vitro, NELX preserved metabolic activity and promoted macrophage polarization toward an anti-inflammatory M2 phenotype, with increased IL10 and IL1RA expression and IL1RA secretion. In vivo, NELX reduced IL6 levels in the air pouch model and suppressed IL6 and IL1β secretion in the pulpitis model, with effects comparable to Ledermix™ Paste. Histology confirmed reduced inflammatory infiltration and enhanced recruitment of CD163+ macrophages. NELX provide a stable and effective delivery system for LXA4, promoting resolution of dental pulp inflammation through targeted immunomodulation. This strategy holds promise for novel biologically based anti-inflammatory therapies in endodontics.