Harnessing Exogenous Stimuli and Functionally 3D Aligned Fibrous Scaffolds for Spatiotemporal Modulation of Bone Regeneration

Bone regeneration requires spatiotemporal coordination of immune modulation, stem cell recruitment, angiogenesis, and osteogenesis, yet most scaffolds lack sequential control across healing phases. We develop a near-infrared (NIR)-responsive therapeutic platform that integrates clinically available irradiation with an engineered 3D radially aligned nanofiber scaffold functionalized with black phosphorus (BP) and a bone marrow mesenchymal stem cell (BMSC)-targeting aptamer (Apt19S). NIR photothermal stimulation accelerates BP degradation, releasing phosphate ions and activating a heat-shock program to promote macrophage polarization, endogenous MSC homing, neovascularization, and osteogenic differentiation. Metabolomics reveals cooperative regulation of HSP-linked signaling and lipid metabolism. In a rat critical-size calvarial defect, the platform achieves robust bone regeneration without exogenous cells or growth factors. The system is simple, structurally tunable, and shape-customizable, providing a clinically translatable and modular framework for spatiotemporal microenvironment programming in bone and other regenerative settings.