Abstract

Bone morphogenetic protein 2 (Bmp2), an FDA-approved osteogenic factor, demonstrates notable potential for enhancing bone regeneration under challenging conditions such as osteoporotic fractures. However, its clinical application is limited by issues including poor in vivo stability and the risk of ectopic ossification. To address these challenges, we developed D-Bmp2@M systems by fusing Bmp2 with a bone-affinity peptide (Asp-Ser-Ser repeated 6 × , DSS6) to generate D-Bmp2, followed by encapsulation of the fusion protein into porous PLGA microspheres. This affinity-based engineering strategy endowed Bmp2 with high bone tissue affinity without compromising bioactivity, thus promoting accelerated fracture healing while reducing the risk of ectopic ossification. Furthermore, the unique multi-chambered porous architecture of the PLGA microspheres enabled a stable, sustained-release profile of D-Bmp2 for approximately 30 days. This release profile not only extends the therapeutic window to align with the fracture healing timeline but also improves treatment efficacy through a cumulative effect, leading to significantly enhanced healing outcomes particularly in osteoporotic fractures. This study presents a PLGA-based sustained-release system that enhances therapeutic efficacy in accelerating fracture healing while reducing Bmp2-associated heterotopic ossification, offering a promising strategy for the treatment of fractures.