Multifunctional 3D-printed Mg-doped bioactive glass/PLLA scaffolds with quercetin delivery for remodeling the osteoporotic microenvironment via osteogenic-angiogenic coupling and osteoclast inhibition.

Osteoporotic bone defects remain challenging to repair due to a dysregulated microenvironment characterized by impaired osteogenesis, insufficient angiogenesis, and excessive osteoclast activity. Herein, we report a multifunctional three-dimensional (3D)-printed scaffold that integrates quercetin-loaded magnesium-doped mesoporous bioactive glass (Mg-BG-Que) into a poly (L-lactic acid) (PLLA) matrix, enabling simultaneous modulation of these pathological features. The composite scaffold affords sustained co-delivery of quercetin and bioactive ions (Mg, Si, Ca, and P), thereby providing both structural support and localized biochemical regulation. In vitro, Mg-BG-Que/PLLA scaffolds significantly promoted osteogenic differentiation of bone marrow mesenchymal stem cells and enhanced endothelial angiogenic activity, while markedly suppressing osteoclast differentiation and resorptive function. Notably, scaffold-mediated regulation of osteoclasts further facilitated angiogenic-osteogenic coupling, revealing a previously underappreciated indirect regulatory mechanism. In an ovariectomy-induced osteoporotic rat model, the scaffold markedly augmented bone regeneration, improved trabecular architecture, elevated the expression of angiogenic and osteogenic markers, and reduced osteoclast-related activity. Collectively, our findings demonstrate that the combination of bioactive ion release with natural small-molecule delivery offers a synergistic strategy for remodeling the osteoporotic microenvironment. The Mg-BG-Que/PLLA scaffold thus represents a promising platform for multifunctional bone regeneration through coordinated regulation of osteogenesis, angiogenesis, and osteoclastogenesis.