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

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.