TRIM30a coordinates neutrophil-macrophage crosstalk to resolve inflammation and drive osseointegration via...

The innate immune response to bone biomaterials critically regulates osteogenesis, yet the molecular mechanisms governing neutrophil-macrophage crosstalk remain poorly understood. Building on our discovery of neutrophil involvement in bone regeneration, we investigated the E3 ubiquitin ligase-Tripartite motif containing protein 30a (TRIM30a) as a potential orchestrator of inflammatory resolution and osseointegration. Through integrated multi-omics analysis of pro-osteogenic versus non-osteogenic metallic implants, we identified TRIM30a as a key regulator. Using conditional knockout mice (whole-body, neutrophil-specific, and macrophage-specific TRIM30a deficiency) combined with NETosis assays and inflammatory signaling profiling, we systematically evaluated TRIM30a's role on NETosis/cGAS-STING axis in bone regeneration, with pharmacological validation using DNase I in murine tibial implant models. TRIM30a expression was positively correlated with the osteogenic ability of pro-osteogenic implants. Mechanistically, TRIM30a suppressed NF-κB/NLRP3 signaling in neutrophils, while synergizing with NET-derived dsDNA to modulate cGAS-STING signaling in macrophages, thereby achieving balanced cytokine production. Therapeutic intervention with DNase I rescued bone formation in TRIM30a-deficient mice, confirming the clinical relevance of this pathway. Our work establishes TRIM30a as a master regulator of bone regeneration through dual mechanisms: restraining neutrophil hyperactivation via NF-κB/NLRP3 inhibition while cooperating with dsDNA to calibrate macrophage cGAS-STING signaling, revealing a targetable immunomodulatory axis for enhancing osseointegration. These findings provide new insights into the immune-bone regeneration interface and suggest novel therapeutic strategies for implant-related bone repair.