Light-Switched Mesenchymal Stem Cells for In Situ Exosome Amplification in Craniofacial Bone Defect Reconstruction

Mesenchymal stem cell (MSC)-based therapies hold great promise for tissue regeneration, yet precise spatiotemporal regulation of their bioactivity remains challenging. Here, we report a light-switchable MSC system (MSC-UCNPs) enabled by intracellular upconversion nanoparticles (UCNPs), which allowed remote control of exosome biogenesis and regenerative function. Upon 980 nm near-infrared irradiation, intracellular UCNPs emitted localized 365 nm ultraviolet light without compromising MSC viability. The generated UVA stimulus activated the ROS/HEXB/LAMP1 signaling cascade, suppressing lysosome-multivesicular body fusion and thereby markedly enhancing exosome production (increased to 2.7-fold). The MSC-derived exosomes exerted autocrine effects to promote MSC proliferation and osteogenic differentiation, while also facilitating osteoblast maturation via activating the Wnt/β-catenin pathway. To facilitate in vivo application, an injectable hydrogel composed of sodium alginate, calcium alginate, and hyaluronic acid was constructed through electrostatic interactions for the localized delivery of MSC-UCNPs. Positron emission tomography-computed tomography (PET-CT) imaging confirmed the in vivo light-switchable behavior of MSC-UCNPs, allowing on-demand enhancement of in situ exosome release. Benefiting from the synergistic regenerative effects of MSCs and their exosomes, this light-responsive MSC platform achieved robust cranial bone regeneration with a 3.2-fold greater bone volume fraction compared to the control group.