Severe traumatic bone healing relies on the involvement of growth factors. However, excessive supplementation of growth factors can lead to ectopic ossification and inflammation. In this study, utilizing the neural regulatory mechanism of bone regeneration, we have developed a multifunctional three dimensions (3D) printed scaffold cont aining both vasoactive intestinal peptide (VIP) and nerve growth factor (NGF) as an effective new method for achieving bone defect regeneration. The scaffold is provided by a controlled biodegradable and biomechanically matched poly(lactide-ethylene glycol-trimethylene carbonate) (PLTG), providing long-term support for the bone healing cycle. Factor loading is provided by peptide fiber-reinforced biomimetic antimicrobial extracellular matrix (ECM) (B-ECM) hydrogels with different release kinetics, the hydrogel guides rapid bone growth and resists bacterial infection at the early stage of healing. Physical and chemical characterization indicates that the scaffold has good structural stability and mechanical properties, providing an ideal 3D microenvironment for bone reconstruction. In the skull defect model, compared to releasing VIP or NGF alone, this drug delivery system can simulate a natural healing cascade of controllable release factors, significantly accelerating nerve/vascular bone regeneration. In conclusion, this study provides a promising strategy for implanting materials to repair bone defects by utilizing neuroregulatory mechanisms during bone regeneration. (c) 2025 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.