Translating m6A‐Glycolysis Discovery into Therapy: GOQD‐Based Multifunctional Bioactive Scaffolds Rejuvenates Bone Repair in Senescence

Abstract Senescence‐related bone regeneration failure arises from the altered fate of senescent BMSCs(s‐BMSCs). This study identified glycolysis dysregulation as a key factor in this process. Mechanistically, the downregulation of METTL3 in s‐BMSCs destabilized ALDH3A1 mRNA, which subsequently triggered ubiquitin‐mediated degradation of c‐Myc—a key regulator of glycolysis. Targeting glycolysis altered s‐BMSCs fate, promoting osteogenic differentiation while inhibiting adipogenesis. Building on the glycolysis‐BMSCs fate relationship, graphene oxide quantum dots (GOQDs) are engineered that demonstrate the ability to potently activate glycolytic flux in s‐BMSCs while concomitantly suppressing macrophage‐mediated inflammatory responses and enhancing angiogenic capacity. Then, a hierarchically porous β‐TCP scaffold is fabricated via 3D printing and subsequently functionalized with GOQDs through polydopamine biointerface‐mediated modification, and BMSCs are integrated into the scaffold by fluid dynamics. This multi‐biofunctional construct accelerates bone regeneration in critical‐sized defects within senescent rat models, evidenced by the restoration of bone tissue compared to senescence‐matched controls. These findings not only establish glycolytic modulation as a key determinant of s‐BMSCs fate but also demonstrate an engineered therapeutic paradigm that simultaneously addresses two critical pathological dimensions: cellular fate dysfunction, vessel‐immune microenvironment disorder in senescence‐related bone regeneration.