3D‐Printable and Bioelectronic‐Compatible Graphene‐Reinforced PLA Nanocomposites Rejuvenate Aged Bone Regeneration Through Glycolytic Reprogramming

Age-related metabolic dysregulation, chronic inflammation, and impaired vascularization severely compromise critical-sized bone healing. Building upon G-PLA nanocomposites previously established for bioelectronic encapsulation, we herein investigate their potential as a bio-instructive interface for guided bone regeneration. Fabricated via in situ graphite exfoliation, G-PLA provides enhanced hydrophilicity, mechanical robustness, and bioactivity while preserving excellent 3D-printability. In rat cranial defects, G-PLA significantly accelerated regeneration, as demonstrated by micro-CT, histological, and immunohistochemical analyses. Comparative evaluations in young and aged animals revealed that G-PLA effectively mitigates age-dependent declines in reparative capacity. Proteomic profiling indicated that G-PLA orchestrates a pro-regenerative microenvironment by inducing glycolytic reprogramming to meet the elevated energy demands of regeneration. In aged defects, G-PLA upregulated glycolytic enzymes (e.g., ALDOA and HK2), enhanced angiogenesis (CD31/CD34), and suppressed inflammation- and senescence-associated markers (e.g., P21 and SIRT2). In vitro studies validated that G-PLA augments glycolytic flux in endothelial cells, enhances osteogenic differentiation of mesenchymal stem cells, and promotes macrophage polarization toward an anti-inflammatory M2 phenotype. Therefore, G-PLA nanocomposites transcend passive structural support to act as a bio-instructive interface that revitalizes the aging-associated vascular-bone coupling, offering a versatile framework for next-generation multifunctional implantable hybrid systems.