Biomimetic nanocomposite cryogel with enhanced peptide binding promotes therapeutic angiogenesis and bone regeneration

•WKYMVm(W) peptide and nWH containing cryogel exhibited osteo-angiogenic properties.•In silico study shows W peptide binding is reliant on sulfation in hyaluronic acid.•sHA based cryogel lead to sustained release of W peptide, contrary to HA cryogel.•W peptide & nWH enhances angiogenesis in hind limb ischemia model, synergistically.•Composite cryogel displayed an enhanced bone regeneration potential. The effective regeneration of large bone defects faces a significant hurdle, primarily due to inadequate vascularization. This study explores the potential of enhancing vascularization and bone regeneration by incorporating whitlockite nanoparticles (nWH; Ca18Mg2(HPO4)2(PO4)12) and WKYMVm (W) peptide into a gelatin-sulfated hyaluronic acid (WH10-W) cryogel. The developed cryogels showed an average pore size of 70 μm. Further, they were characterized for degradation rate, swelling ratio, mechanical and rheological properties. The WH10-W group exhibited sustained release of the W peptide, in contrast to the rapid release observed from gelatin-hyaluronic acid. In silico binding studies revealed that the binding of the W peptide was dependent on the sulfation degree in hyaluronic acid. The prepared cryogels were cytocompatible. The combinatorial group (WH10-W) demonstrated superior pro-angiogenic compared to cryogel with only nWH or W peptide, as seen from tube formation assay, scratch test and gene expression studies. In addition, WH10-W enhanced the osteogenic differentiation as seen from the osteogenic gene expression, ALP and alizarin red s staining. Finally, mouse hind limb ischemia model demonstrated enhanced angiogenic potential, while a mouse cranial defect study showed increased new bone formation in the WH10-W group compared to all other groups. These findings suggest a promising strategy for addressing large non-load bearing bone defects.