A tetrahedral DNA nanostructure-mediated miRNA inhibitor delivery system: Type H vessel-related bone healing during distraction osteogenesis

A schematic depiction outlining the proposed mechanisms underlying the angiogenic and osteogenic effects of TDN and TDN@miR205 within the context of distraction osteogenesis (DO). [Display omitted] •A novel and effective miRNA delivery system, TDN@miRNA205, has been developed for bone healing.•A novel biological process involving TDN in bone regeneration: TDN and TDN@miR205 regulate osteogenic differentiation via vascularization.•TDN and TDN@miRNA205 activate TGF-β/BMP signaling and elevate both osteogenic and angiogenic functions.•The TDN or TDN@miRNA205 offer broad potential for Distraction osteogenesis. The clinical treatment of critical bone defects presents a great challenge, and distraction osteogenesis (DO) emerges as a highly effective strategy. However, prolonged consolidation periods resultant complications limit its clinical applicability. MicroRNA (miR) therapeutic strategies, with a notable focus on miR-205, demonstrate significant potential during DO. Nevertheless, the limited cellular uptake and facile biodegradation of miRNA constrain its applications. To address these challenges, we introduce tetrahedral DNA nanostructure (TDN), an innovative nanomaterial, engineered as gene carriers. TDN delivers the miR-205 inhibitor (TDN@miR205) to synthesize the novel nanoparticles that support bone healing for the first time. TDN@miR205 enhances the osteogenic potential of bone marrow-derived mesenchymal stem cells (BMSCs), whereas TDN alone is ineffective. Further exploration reveals TDN-modulated angiogenesis-osteogenesis communication, establishing a crucial intercellular regulatory mechanism. Notably, TDN@miR205 expedites bone formation by promoting type H vessels-related angiogenesis, secreting SLIT3 to inhibit osteoclasts, inducing SDF1 homing of BMSCs, then upregulating osteogenic genes and proteins via the TGF-β/BMP pathway, facilitating early bony ossification both in vitro and in vivo. In conclusion, TDN@miR205, the multifunctional nanoparticle-mediated vascular bone regeneration significantly contributes to ossification in DO and establishes this platform as a promising and versatile strategy for addressing DO and other complex bone diseases.