Immunotherapies based on macrophage reprogramming in periodontitis and apical periodontitis

Introduction: Periodontitis and apical periodontitis (AP) are characterized by biofilm-driven, immune-mediated bone destruction. Macrophages orchestrate the immune imbalance, where the M1/M2 polarization axis is critical for tissue homeostasis. Aim: To review preclinical strategies for macrophage reprogramming-based immunotherapies in periodontitis and AP. Methods: A literature search in Web of Science (last 10 years) identified original in vivo and complementary in vitro studies evaluating interventions targeting macrophage polarization. Eligible studies reported M1 markers (CD80, CD8, and/or iNOS) and M2 markers (CD163, CD206, and/or Arg-1) in relation to inflammatory modulation and regenerative outcomes. Results: Fifteen studies met the criteria. In periodontitis, local therapeutic strategies such as bioactive cytokines (CCL2, IL-37), inhibition of extracellular matrix proteins (FBLN3), functionalized biomaterials (Se-nHA/PC microspheres, Q@MPDA nanoparticles), MSC-derived exosomes, regulatory miRNAs (miR-126), pharmacological agents (glipizide, apabetalone), and adoptive M2 transfer demonstrated M2 polarization. In AP, systemically administered M2-derived extracellular vesicles, pharmacological agents (DMOG, Stattic, azithromycin), and blockade of Gremlin-1 are associated with M2 phenotypes. All reduced alveolar bone loss, osteoclast activity, and pro-inflammatory mediators, while favoring reparative responses. Mechanistically, effects were mediated through MAPKs, PI3K/Akt/HIF-1α, STAT3, and NF-κB pathways. Conclusions: Current evidence highlights macrophage reprogramming toward an M2 phenotype as a promising adjunctive strategy for periodontitis and AP. Delivered locally or systemically, these interventions dampen M1-driven inflammation and enhance regeneration, though validation in orthotopic models and translational studies remains necessary. Clinical relevance: Immunotherapeutic approaches targeting macrophage polarization could complement conventional biofilm control with emphasis on regenerative periodontics and endodontic procedures, opening new avenues for biologically driven, patient-centered therapies.