Mandibular osteoradionecrosis (ORN), characterized by extensive and irreversible bone necrosis secondary to ionizing radiation, is a serious complication of radiotherapy treatment. For these patients, therapeutic options are limited due to a severe bone ischemia associated with a cancerous context. Consequently, the development of innovative biotherapies targeting both osteogenesis and angiogenesis is essential to enable satisfactory bone repair. Bone Morphogenetic Proteins 2/4/7 (BMPs), known for their angio- and osteo-genetic properties, have been widely studied for bone regenerative medicine strategies. However, these are characterized by high cost and require supra-physiological doses, this combined with their pro-proliferative activity makes them impossible to use in a tumoral context. Matrix GLA protein (MGP), an inhibitor of BMPs in a proline64 (Pro64) dependent manner, also possesses GLA domains responsible for anti-calcification activity. Our data have shown that mice model carrying a p.P64G mutation (MgpKiPro64) exhibits increased vasculogenesis and osteogenesis, without ectopic vascular calcification. These findings suggest that modulation of the BMPs/MGP interaction could promote bone and vascular growth without the adverse effects associated with the use of exogenous BMPs. Hence, the objectives of this project are to: 1) screen peptide inhibitors that can block the interaction between MGP and BMPs; 2) functionalize an injectable bone substitute; and 3) assess its efficiency in treating ORN in rodents. Therefore, identifying the interaction zone between BMPs and MGPs accurately by utilizing a peptide-based inhibitor while preserving the GLA domains could provide an encouraging approach to improving the bioavailability and consequently the bioactivity of endogenous BMPs for patients struggling with ORN.