Lactate-functionalized 3D-printed PCL/nHA scaffold drives BMSC osteogenesis via metabolic-epigenetic crosstalk

Critical-sized bone defects pose significant clinical challenges due to the limited regenerative potential of human bone mesenchymal stem cells (BMSCs). To address this, we developed a 3D-printed polycaprolactone/nano-hydroxyapatite scaffold functionalized with sodium lactate (PCL/nHA/SL) to synergistically integrate structural support with metabolic-epigenetic modulation. The lactate-functionalized scaffold demonstrated excellent biocompatibility, facilitating BMSC adhesion, proliferation, and osteogenic differentiation. Compared to non-functionalized controls, the PCL/nHA/SL scaffold markedly enhanced osteogenesis, as evidenced by accelerated mineralization and upregulation of key osteogenic markers. Proteomic analysis revealed that lactate incorporation induced lysine lactylation modifications, with STAT1 identified as a central regulatory target. Mechanistic studies established that lactylation redirected STAT1 subcellular localization, thereby liberating RUNX2 to activate osteogenic transcriptional programs. Genetic validation underscored the critical role of STAT1 lactylation in orchestrating this metabolic-epigenetic crosstalk. In vivo evaluations further demonstrated the scaffold's capacity to drive functional bone regeneration in critical-sized defects, achieving robust trabecular bone formation. This study introduces a novel biomaterial strategy that couples 3D-printed architecture with lactate-driven metabolic reprogramming to overcome intrinsic barriers in BMSC-mediated osteogenesis. The findings highlight the potential of metabolic-epigenetic engineering in bone tissue regeneration and provide a translatable platform for complex defect repair. This illustration depicts a 3D-printed PCL/nHA scaffold releasing lactate to drive BMSC metabolic reprogramming and STAT1 lactylation. Cytoplasmic STAT1 relocation activates nuclear Runx2, triggering osteogenic gene expression. In vivo, the PCL/nHA/SL scaffold regenerates critical-sized bone defects with mature trabeculae.