Spatiotemporal Delivery of pBMP2 and pVEGF by a Core–Sheath Structured Fiber‐Hydrogel Gene‐Activated Matrix Loaded with Peptide‐Modified Nanoparticles for Critical‐Sized Bone Defect Repair

The clinical translation of bioactive scaffolds for the treatment of large segmental bone defects remains a grand challenge. The gene-activated matrix (GAM) combining gene therapy and tissue engineering scaffold offers a promising strategy for the restoration of structure and function of damaged or dysfunctional tissues. Herein, a gene-activated biomimetic composite scaffold consisting of an electrospun poly(ε-caprolactone) fiber sheath and an alginate hydrogel core which carried plasmid DNA encoding bone morphogenetic protein 2 (pBMP2) and vascular endothelial growth factor (pVEGF), respectively, is developed. A peptide-modified polymeric nanocarrier with low cytotoxicity and high efficiency serves as the nonviral DNA delivery vector. The obtained GAM allows spatiotemporal release of pVEGF and pBMP2 and promotes osteogenic differentiation of preosteoblasts in vitro. In vivo evaluation using a critical-sized segmental femoral defect model in rats shows that the dual gene delivery system can significantly accelerate bone healing by activating angiogenesis and osteogenesis. These findings demonstrate the effectiveness of the developed dual gene-activated core-sheath structured fiber-hydrogel composite scaffold for critical-sized bone defect regeneration and the potential of cell-free scaffold-based gene therapy for tissue engineering.