2. Academic Validation
  3. Selective promotion of sensory innervation-mediated immunoregulation for tissue repair

Selective promotion of sensory innervation-mediated immunoregulation for tissue repair

  • Sci Adv. 2025 Mar 21;11(12):eads9581. doi: 10.1126/sciadv.ads9581.
Kaicheng Xu 1 2 3 4,  Kaile Wu 1 2 3 4,  Liang Chen 1 2 3 4,  Yubin Zhao 1 2 3 4,  Hengyuan Li 1 2 3 4,  Nong Lin 1 2 3 4,  Zhaoming Ye 1 2 3 4,  Jianbin Xu 1 2 3 4,  Donghua Huang 1 2 3 4,  Xin Huang 1 2 3 4
Affiliations

Affiliations

  • 1 Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 2 Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, China.
  • 3 Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, China.
  • 4 Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, Zhejiang, China.
PMID: 40117376 DOI: 10.1126/sciadv.ads9581
Abstract

Sensory innervation triggers the regenerative response after injury. However, dysfunction and impairment of sensory nerves, accompanied by excessive inflammation impede tissue regeneration. Consequently, specific induction of sensory innervation to mediate immunoregulation becomes a promising therapeutic approach. Herein, we developed a cell/drug-free strategy to selectively boost endogenous sensory innervation to harness immune responses for promoting tissue rehabilitation. Specifically, a dual-functional phage was constructed with a sensory nerve-homing peptide and a β-subunit of nerve growth factor (β-NGF)-binding peptide. These double-displayed phages captured endogenic β-NGF and localized to sensory nerves to promote sensory innervation. Furthermore, regarding bone regeneration, phage-loaded hydrogels achieved rapid sensory nerve ingrowth in bone defect areas. Mechanistically, sensory neurotization facilitated M2 polarization of macrophages through the Sema3A/XIAP/PAX6 pathway, thus decreasing the M1/M2 ratio to induce the dissipation of local inflammation. Collectively, these findings highlight the essential role of sensory innervation in manipulating inflammation and provide a conceptual framework based on neuroimmune interactions for promoting tissue regeneration.

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