Large segmental osseous defects heal poorly, creating major medical, social and economic issues. Although several clinical options for healing such defects exist, all have major disadvantages. We describe a novel approach to bone regeneration using chemically modified messenger RNA (cmRNA). An optimized cmRNA encoding bone morphogenetic protein 2 (BMP-2) was delivered to critical size, mid-diaphyseal, femoral osteotomies in rats. The cmRNA remained orthotopically localized and generated BMP locally for several days. Defects healed at doses > 25 µg BMP-2 cmRNA. By four weeks, all animals treated with 50 µg BMP-2 cmRNA had bridged bone defects without forming the massive callus seen with rhBMP-2. Transcriptomic analysis and immunohistochemistry confirmed that cmRNA regenerated bone via endochondral ossification, whereas rhBMP-2 drove intramembranous bone formation. The osteogenic properties of the optimized cmRNA were superior to those of rhBMP-2 and provide the basis of an innovative, safe and highly translatable technology for healing osseous defects.