The miR-212-3p/transferrin axis promotes bone regeneration by modulating iron homeostasis through Schwann cell Exosome-BMSCs communication.

Functional bone regeneration relies on cross talk between nerves and bone, yet the regulatory mechanisms linking Schwann cells (SCs) to osteoporotic bone marrow mesenchymal stem cells (OP-BMSCs) remain unclear. This study demonstrated that SC-Exosomes (Exos) promoted the osteogenic differentiation of OP-BMSCs, and miRNA-mRNA sequencing revealed that SC-Exos, which contained the key mediator miR-212-3p, facilitated osteogenesis by suppressing the ferroptosis pathway in OP-BMSCs. miR-212-3p overexpression combined with transferrin (TF) knockdown or overexpression confirmed that miR-212-3p suppresses TF expression and validated the role of the miR-212-3p/TF axis, which maintained iron homeostasis in BMSCs, alleviated iron overload and oxidative stress, and promoted osteogenic differentiation. Furthermore, an injectable SC-Exos-loaded gelatin methacrylate hydrogel (SC-Exos/GelMA) targeting BMSCs was constructed. In vitro, SC-Exos/GelMA enabled sustained release of Exos and promoted BMSCs osteogenesis. In vivo, SC-Exos/GelMA downregulated TF expression via the miR-212-3p/TF axis, mitigated ferroptosis, restored iron homeostasis, accelerated angiogenesis/neurogenesis, and promoted bone regeneration. This study not only elucidated the role of the miR-212-3p/TF axis in the modulation of BMSCs iron homeostasis, but also constructed an injectable SC-Exos/GelMA hydrogel for bone regeneration, offering mechanistic insights and a translational therapeutic strategy for bone regeneration in clinic.