Immune Microenvironment Engineering for Functional Periodontal Regeneration: Mechanisms, Biomaterial Strategies, and Translational Perspectives.

Periodontitis is a chronic inflammatory disease characterized by irreversible destruction of alveolar bone, periodontal ligament attachment, and supporting tooth structures. Emerging evidence suggests that periodontal tissue breakdown and regenerative failure are primarily driven by dysregulation of the local immune microenvironment rather than by direct bacterial insult. Therefore, conventional therapies focused primarily on microbial control are insufficient to restore immune homeostasis and functional regeneration of the cementum-periodontal ligament-alveolar bone complex. Effective periodontal regeneration requires coordinated infection management, immune modulation, oxidative stress clearance, and inflammatory microenvironment reprogramming to relieve the suppression of regenerative cells, particularly periodontal ligament stem cells. This review summarizes key regulatory networks of the periodontal immune microenvironment, with emphasis on macrophage polarization, neutrophil heterogeneity, and the imbalance between Th17 cells and regulatory T cells. We further discuss recent immune-engineering strategies for restoring periodontal homeostasis, including surface-modified biomaterials, ion-delivery systems, stem cell-derived extracellular vesicles, gene-editing technologies, and smart responsive therapeutic scaffolds. Advances in single-cell and spatial transcriptomics have revealed previously unrecognized functional subpopulations, such as NLRP3+ macrophages and SAA1+ fibroblasts, offering new opportunities for precision immunomodulation. Collectively, this review provides an integrated and translational framework for leveraging immune microenvironment-based interventions to achieve functional and predictable periodontal regeneration.