Selective promotion of sensory innervation-mediated immunoregulation for tissue repair

Sci Adv. 2025 Mar 21;11(12):eads9581. doi: 10.1126/sciadv.ads9581. Epub 2025 Mar 21.

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.

MeSH terms

  • Animals
  • Bone Regeneration
  • Humans
  • Hydrogels / chemistry
  • Inflammation
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mice
  • Nerve Growth Factor / metabolism
  • Nerve Regeneration*
  • Semaphorin-3A / metabolism
  • Sensory Receptor Cells* / immunology
  • Sensory Receptor Cells* / metabolism
  • Wound Healing*

Substances

  • Nerve Growth Factor
  • Hydrogels
  • Semaphorin-3A