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

ABSTRACT 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.