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Periodontitis and apical periodontitis are traditionally approached as biofilm-driven diseases, where treatment is largely centered on microbial control. However, clinical and experimental evidence increasingly shows that eliminating or reducing the microbial challenge is only part of the story. Successful healing also requires resolution of inflammation and restoration of local immune homeostasis.

This was the starting point for our review published in Clinical Oral Investigations (10.1007/s00784-026-06918-4). We were interested in examining whether macrophages — highly plastic immune cells with central roles in both tissue destruction and repair — could be therapeutically reprogrammed to shift the inflammatory microenvironment toward resolution and regeneration.

In this review, we analyzed preclinical studies evaluating macrophage-targeted immunotherapeutic strategies in periodontitis and apical periodontitis. These approaches included soluble immunomodulatory mediators, inhibition of inflammatory signaling pathways, extracellular vesicle-based strategies, regulatory nucleic acids, pharmacological modulation, functionalized biomaterials, and cell-based interventions.

Across these studies, macrophage reprogramming toward pro-resolving and reparative phenotypes was associated with reduced inflammatory mediator expression, decreased osteoclast activity, attenuation of periodontal or periapical bone loss, and enhanced tissue repair. In apical periodontitis models, some strategies also supported biological processes relevant to periradicular healing and root development, including cementogenic, odonto/osteogenic, angiogenic, and neurogenic responses.

Together, these findings support macrophage-targeted immunotherapy as a promising adjunctive strategy to conventional periodontal and endodontic treatment. Immune modulation may help create a biological environment that is more permissive to tissue repair and regeneration.