Remote Control of Intracellular Calcium Using Upconversion Nanotransducers Regulates Stem Cell Differentiation In Vivo

Remote control of stem cell differentiation in vivo by stimuli‐responsive nanomaterials with the use of tissue‐penetrative stimuli is an appealing strategy for versatile regulation in stem cell therapy. In this study, an upconversion nanotransducer (UCNT)‐based nanocomplex with photolabile caging of chondro‐inductive kartogenin (KGN) and/or either calcium chelator or calcium supplier (caged calcium), and subsequent coupling of integrin‐binding ligand via cyclodextrin‐adamantine supramolecular complexation is utilized. Near‐infrared (NIR)‐to‐ultraviolet light conversion by UCNT nanocomplex triggered intracellular photo‐uncaging and release of cargo molecules, thereby allowing direct regulation of real‐time intracellular calcium levels. While intracellular KGN delivery led to the differentiation of human mesenchymal stem cells (hMSCs) into hypertrophic chondrocytes, NIR‐regulated intracellular calcium decrease and KGN delivery induced their differentiation into chondrocytes by inhibiting hypertrophy. Conversely, intracellular calcium increase and KGN delivery promoted the differentiation of hMSCs into osteoblasts via endochondral pathway. To the best of knowledge, this is the first demonstration of utilizing NIR‐controllable nanomaterials for regulating stem cell differentiation by controlling intracellular calcium, both in vitro and in vivo. This versatile control can facilitate the translation of stem cells to remotely controlled treatment of diseases in composite tissues involving various cell types. An upconversion nanotransducer‐based nanocomplex to directly regulate real‐time intracellular calcium levels by near‐infrared light is developed, to manipulate an endochondral differentiation pathway in stem cells. It is demonstrated that this nanocomplex can remotely direct differentiation of human mesenchymal stem cells into hypertrophic chondrocytes, chondrocytes, and osteoblasts, both in vitro and in vivo.