Why Peri‐Implant Tissues Are Susceptible to Inflammatory Breakdown—Single‐Cell Transcriptomics Reveals Immune Priming in Clinically Healthy Peri‐Implant Mucosa and CXCR2 + Neutrophil Activation in Peri‐Implantitis

ABSTRACT Aim Peri‐implant tissues are more susceptible than gingiva to rapid inflammatory breakdown, but the cellular basis of this vulnerability remains unclear. This study investigated (1) whether clinically healthy peri‐implant mucosa already displays an immune landscape distinct from healthy gingiva, and (2) which cellular states and molecular pathways characterize the transition from peri‐implant health to peri‐implantitis. Methods An integrative single‐cell RNA‐sequencing analysis was performed using clinically healthy pre‐loading peri‐implant mucosa ( n = 3), healthy gingiva ( n = 17), and peri‐implantitis tissues ( n = 3). Healthy peri‐implant mucosa was first compared with a healthy gingival reference atlas to define the baseline peri‐implant immune niche. Disease‐associated changes were then examined by comparing healthy peri‐implant and peri‐implantitis tissues. Key findings were validated in independent tissue cohorts comprising healthy gingiva, clinically healthy peri‐implant mucosa, and peri‐implantitis ( n = 6 participants per group) using multiplex immunofluorescence, immunohistochemistry, and reactive oxygen species (ROS) detection. Results Clinically healthy peri‐implant mucosa showed greater immune‐cell enrichment than healthy gingiva, most notably within the myeloid compartment. Among myeloid cells, a CXCR2 + neutrophil subset exhibited the highest baseline signature for neutrophil extracellular trap (NET) formation, indicating an immune‐enriched state with enhanced NET‐associated transcriptional potential, despite clinical health. In peri‐implantitis, this CXCR2 + neutrophil subset expanded further and displayed increased oxidative, chemotactic, and NET‐associated programs, supported by tissue validation of MPO, CXCR2, CitH3, and ROS signals. Cell–cell communication analysis nominated fibroblast‐derived CXCL signaling as a potential contributor to CXCR2 + neutrophil recruitment. NSUN6, an RNA modification enzyme, was enriched in disease‐associated CXCR2 + neutrophils, and NSUN6 knockdown in neutrophil‐like cells attenuated CXCR2 + cell enrichment and NET‐associated marker expression. Conclusion Clinically healthy peri‐implant mucosa before functional loading is not immunologically equivalent to gingiva, but represents an immune‐primed niche that may lower the threshold for inflammatory breakdown. These findings may not be directly generalized to long‐term functionally loaded implants. Peri‐implantitis is characterized by amplification of an oxidative CXCR2 + neutrophil state, with fibroblast‐derived CXCL–CXCR2 signaling and NSUN6‐associated neutrophil activation emerging as candidate pathways for future diagnostic and therapeutic investigation.