Near-infrared light-triggered release of small molecules for controlled differentiation and long-term tracking of stem cells in vivo using upconversion nanoparticles.

Human mesenchymal stem cells (hMSCs) hold considerable potential for regenerative medicine, but their application is limited by the lack of an efficient method to control differentiation and track the migration of implanted cells in vivo. In this study, we developed a multifunctional nanocarrier based on upconversion nanoparticles (UCNPs) for controlling differentiation and long-term tracking of hMSCs. The UCNPs are conjugated with the peptide (Cys-Arg-Gly-Asp, CRGD) and the differentiation-inducing kartogenin (KGN) via a photocaged linker on the surface, and the obtained UCNP nanocarrier can be efficiently uptaken by hMSCs. Under the exposure of near-infrared (NIR) light, the upconverted UV emission from the UCNP nanocarrier leads to the photocleavage of the photocaged linker and intracellular release of KGN. The NIR-triggered release of KGN mediated by the UCNP nanocarrier efficiently induces chondrogenic differentiation of hMSCs in vitro with reduced KGN dosage compared to the conventional protocol of directly supplementing KGN in the media. Furthermore, NIR irradiation through the skin of living animals induces the chondrogenic differentiation of the subcutaneously implanted hMSCs treated with the KGN-laden UCNP nanocarrier, thereby enhancing neocartilage formation in vivo. Finally, the luminescent UCNP nanocarrier enables the long-term tracking of the labeled hMSCs in vivo. We believe that our UCNP nanocarrier is a promising tool for the remote control of triggered delivery of inductive agents to stem cells at the prescribed time points and the elucidation of the function and the fate of the transplanted stem cells in vivo.