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Anxiety is clinically linked to impaired fracture healing, but its underlying immune mechanisms are still unclear, and there’s currently no targeted treatment. In a mouse model with chronic restraint stress (CRS)-induced anxiety combined with femoral fractures, we observed an expansion of TGFβ1CCR5 double-positive neutrophils in the bone marrow. These neutrophils inhibit the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) by secreting TGFβ1, while CCL5 derived from BMSCs promotes neutrophil activation in return, forming a harmful feedback loop that disrupts fracture repair. Mechanistically, CRS activates the NF-κB–CCR5 axis, which upregulates CCR5 and maintains this neutrophil subpopulation. We found that acetyl-11-keto-β-boswellic acid (AKBA) directly binds YAP1, relieving YAP1-mediated inhibition of ubiquitin-specific protease 31 (USP31), thereby suppressing NF-κB phosphorylation and CCR5 expression, reducing pathogenic neutrophil populations, and restoring BMSC osteogenic function. To overcome AKBA’s poor solubility, low bioavailability, and non-specific tissue distribution, we developed NIMP-R14 aptamer-modified EGCG-coated nanocarriers (AKBA@E-N), which enhance the local uptake and retention of neutrophils in the acidic microenvironment at the fracture site. In vivo, AKBA@E-N significantly accelerated fracture healing compared to free AKBA. This study reveals a neutrophil-mediated mechanism linking stress to impaired bone repair and offers a targeted anti-stress therapeutic strategy.
References:
DOI:10.1016/j.bioactmat.2026.09.028
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