Periodontal immune homeostasis: neutrophils as guardians and betrayers, and strategies for precision modulation.

The health of periodontal tissues fundamentally depends on a delicate, dynamic immune homeostasis; disruption of this balance constitutes the pathological basis driving the initiation and progression of chronic periodontitis. Due to their high heterogeneity and phenotypic plasticity, neutrophils play multifaceted roles in maintaining periodontal homeostasis and driving disease progression. Under homeostatic conditions, through precisely regulated mechanisms including chemotaxis, phagocytosis, and extracellular trap formation, neutrophils actively clear microorganisms and sustain tissue tolerance. However, under persistent microbial challenge and the influence of host factors, overactivated neutrophils exacerbate periodontal tissue destruction via mechanisms such as excessive neutrophil extracellular trap (NET) formation, uncontrolled release of pro-inflammatory mediators, and induction of osteoclastogenesis. This review systematically elucidates the role and mechanisms of neutrophils in the establishment, disruption, and restoration of periodontal immune homeostasis. It comprehensively evaluates emerging neutrophil-targeted therapeutic strategies, including modulation of their antimicrobial activity, chemotaxis, activation, secretory phenotypes, apoptosis, and clearance. Finally, this review summarizes current strategies for constructing time-sequential drug delivery systems in periodontitis. This review aims to provide novel perspectives for developing a comprehensive, multi-dimensional neutrophil regulatory model and for clinical applications and further research focused on re-establishing periodontal homeostasis.