Methotrexate loaded extracellular vesicles attenuate periodontitis by suppressing ACSL1 and promoting anti-inflammatory macrophage.

Macrophages are crucial immune cells in periodontal tissues, which play key roles in both the destruction and repair of associated with periodontitis. Targeted modulation of macrophage function has emerged as a potentially effective approach to influence periodontitis progression. This study investigates the effects of methotrexate-loaded extracellular vesicles (MTX-EVs) on inflammatory macrophage polarization both in vivo and in vitro. In a murine periodontitis model, MTX-EVs inhibited alveolar bone resorption, suppressed pro-inflammatory macrophage activation, and promoted anti-inflammatory macrophages. Mechanistically, MTX-EVs reduced acyl-CoA synthetase-1 (ACSL1) expression, which was elevated during inflammation. Inhibition of ACSL1 with triacsin-C in macrophages suppressed the inflammatory phenotype through the promotion of the oxidative phosphorylation (OXPHOS). In contrast, MTX-EVs counteracted the effects of ACSL1 overexpression on macrophage polarization and metabolism. Our findings suggest that targeting ACSL1 via MTX-EVs represents a therapeutic strategy for modulating macrophage polarization and improving periodontitis treatment outcomes.