Bioengineered apoptotic vesicles overcome energy crisis in bone regeneration through mitochondrial metabolic activation.

Abstract

Bone regeneration faces dual challenges of insufficient energy supply and oxidative stress, while both energy provision and reactive oxygen species levels are mitochondrially regulated and tend to increase or decrease synchronously. Conventional biomaterials fail to reconcile the high ATP demands of osteogenesis with mitochondrial dysfunction. Here, we present laponite-primed apoptotic vesicles (L@Apo) derived from bone marrow mesenchymal stem cells (BMSCs), engineered to address this bioenergetic crisis through dual-pathway mitochondrial regulation. L@Apo integrates more mitochondrial components and bioactive factors with cargo delivery to activate PINK1/Parkin-mediated mitophagy, selectively eliminating dysfunctional mitochondria while initiating biogenesis to replenish energetic capacity. Concurrent PI3K-/AKTsignaling drives metabolic rewiring, amplifying both glycolysis and oxidative phosphorylation to meet mineralization demands. A thiol-ene hydrogel (L@Apo-G/P) ensures sustained vesicle release, preserving mitochondrial integrity and bioactivity. In vitro, L@Apo promotes osteogenic differentiation, angiogenesis, and anti-inflammatory macrophage polarization while mitigating oxidative damage. In vivo, L@Apo-G/P achieves robust bone regeneration in rat femoral defects, surpassing conventional strategies in structural and functional restoration. This biomaterial platform enhances energy metabolism and reduces oxidative damage through programmable mitochondrial reprogramming, establishing a viable strategy for regenerating tissues with high metabolic demands.