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Peer-reviewedCC BYAdvanced science (Weinheim, Baden-Wurttemberg, Germany)

Reln mRNA Delivery Drives Neurogenic Bone Regeneration by Orchestrating Schwann Cell-Mediated Exosomal Trafficking.

  • Shuai Lin
  • Qianwen Li
  • Duo Liu
  • Mingzhao Li
  • Han Zhang
  • Liujing Chen
  • Yan Yu1,2
  • Jiuhui Jiang
  • Chun Xu1,2
  • Ruili Yang3
  1. 1Sydney Dental School, Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia.
  2. 2Charles Perkins Centre, The University of Sydney, Camperdown, Australia.
  3. 3School of Stomatology Sanya Division (Sanya Stomatology Center), Peking University, Sanya, Hainan, China.
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Abstract

Neurogenic bone regeneration is essential for the effective restoration of bone tissue functionality, while the mechanisms and new strategies underlying neurogenic bone regeneration remain to be further explored. Here, single-cell transcriptomic analysis revealed enhanced mesenchymal-Schwann cell crosstalk during bone regeneration. Functionally, we verify that Schwann cells are indispensable for bone regeneration via paracrine exosome-mediated crosstalk with MSCs, a process promoted by Reelin. Mechanistically, Reelin enhances Schwann cell-derived exosome internalization by MSCs via regulating exosomal proteins, especially UBE2K, which promotes MSC osteogenic differentiation through the ERK pathway, associated with Lys63-linked polyubiquitination. For effective neurogenic bone regeneration, we engineered mesoporous silica nanoparticles (MSNs) as a CRISPRa delivery system for local Reln gene activation at the defect area. This mRNA delivery system could promote bone regeneration in both calvarial defect and tibial fracture models by constructing a pro-osteogenic neurogenic microenvironment. Collectively, our findings uncover a Reelin-Schwann cell exosomes-ERK regulatory axis in bone regeneration with translational potential, highlighting the therapeutic value of targeting neural-osteogenic crosstalk in bone regeneration.

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Cite

BibTeXRIS
BibTeX
@article{lin2026reln,
  title = {{Reln mRNA Delivery Drives Neurogenic Bone Regeneration by Orchestrating Schwann Cell-Mediated Exosomal Trafficking.}},
  author = {Shuai Lin and Qianwen Li and Duo Liu and Mingzhao Li and Han Zhang and Liujing Chen and Yan Yu and Jiuhui Jiang and Chun Xu and Ruili Yang},
  journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
  year = {2026},
  month = nov,
  doi = {10.1002/advs.78530},
  url = {https://europepmc.org/article/MED/42969166},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Reln mRNA Delivery Drives Neurogenic Bone Regeneration by Orchestrating Schwann Cell-Mediated Exosomal Trafficking.
AU  - Shuai Lin
AU  - Qianwen Li
AU  - Duo Liu
AU  - Mingzhao Li
AU  - Han Zhang
AU  - Liujing Chen
AU  - Yan Yu
AU  - Jiuhui Jiang
AU  - Chun Xu
AU  - Ruili Yang
PY  - 2026
DA  - 2026/11/02
JO  - Advanced science (Weinheim, Baden-Wurttemberg, Germany)
DO  - 10.1002/advs.78530
UR  - https://europepmc.org/article/MED/42969166
AB  - Neurogenic bone regeneration is essential for the effective restoration of bone tissue functionality, while the mechanisms and new strategies underlying neurogenic bone regeneration remain to be further explored. Here, single-cell transcriptomic analysis revealed enhanced mesenchymal-Schwann cell crosstalk during bone regeneration. Functionally, we verify that Schwann cells are indispensable for bone regeneration via paracrine exosome-mediated crosstalk with MSCs, a process promoted by Reelin. Mechanistically, Reelin enhances Schwann cell-derived exosome internalization by MSCs via regulating exosomal proteins, especially UBE2K, which promotes MSC osteogenic differentiation through the ERK pathway, associated with Lys63-linked polyubiquitination. For effective neurogenic bone regeneration, we engineered mesoporous silica nanoparticles (MSNs) as a CRISPRa delivery system for local Reln gene activation at the defect area. This mRNA delivery system could promote bone regeneration in both calvarial defect and tibial fracture models by constructing a pro-osteogenic neurogenic microenvironment. Collectively, our findings uncover a Reelin-Schwann cell exosomes-ERK regulatory axis in bone regeneration with translational potential, highlighting the therapeutic value of targeting neural-osteogenic crosstalk in bone regeneration.
SN  - 2198-3844
ER  -