Reln mRNA Delivery Drives Neurogenic Bone Regeneration by Orchestrating Schwann Cell‐Mediated Exosomal Trafficking
Year: 2026
Type: article
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.
Source: Advanced Science
DOI: 10.1002/advs.78530
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,730
OpenAlex ID: W7225122004