Non-healing bone defects remain a significant problem for combat casualties and military veterans. A principle challenge is to develop therapeutic agents that safely and effectively improve growth and differentiation factor (GDF) based skeletal regeneration. The manipulation of Hedgehog signaling is a promising alternative to BMP2 for improved bone repair outcomes. Recently, we observed thatthe small molecule Hedgehog agonist SAG demonstrates pro-osteogenic / pro-vasculogenic effects to induce mouse calvarial defect healing. Independently, we have developed innately osteoinductive Stearylamine and Oxysterol (SA/Oxy) nanoparticles (NPs), and showed their high drug loading efficiency and synergistic osteoinductive potential with the small molecule SAG. In the current proposal, we willcombine these recent breakthroughs to develop a next generation NP packaged small molecule as a bone graft substitute product to jumpstart endogenous bone repair.