Near-infrared light-responsive upconversion substrate enables spatiotemporal control of mesenchymal stem cells...

Spatiotemporally precise control of mesenchymal stem cells (MSCs) differentiation remains an unmet challenge in regenerative medicine. Herein, we report a near-infrared (NIR)-responsive platform that integrates upconversion nanoparticle (UCNP)-functionalized substrates with host-guest photoresponsive chemistry (β-cyclodextrin/arylazopyrazole-RGD) to NIR spatiotemporally orchestrate MSCs adhesion, spreading, and lineage commitment with spatiotemporal precision. The UCNPs convert 808 nm NIR light into localized UV emissions, dynamically modulating azobenzene-cyclodextrin interactions and thereby tuning surface RGD ligand density via photoisomerization. Under low NIR intensities (0-0.5 W/cm²), augmented integrin-RGD binding drives robust focal adhesion assembly, actin cytoskeletal tension, nuclear YAP translocation, and osteogenic differentiation, as evidenced by 2-3 fold upregulation of BMP2, RUNX2, and ALP. Conversely, high-intensity NIR (1-2 W/cm²) induces RGD detachment, leading to suppressed cytoskeletal contractility and nuclear Lamin A/C expression, consequent cytoplasmic YAP retention, and activation of PPARγ-mediated adipogenesis, marked by 4-5 fold induction of PPARγ, C/EBPα, and FABP4. Most importantly, in vivo murine studies validate the platform's capacity for non-invasive, light-guided spatiotemporal regulation of MSCs adhesion, spreading, YAP signaling, and lineage specification (osteogenic vs. adipogenic), wherein differentiation thresholds (e.g., 1 W/cm²) correspond to clinically safe NIR exposure limits. This opto-material hybrid system effectively decouples photochemical stimulation to program MSC fate via mechanotransduction pathways, thereby providing a translatable strategy for the design of intelligent biomaterials towards personalized tissue regeneration.