Spatiotemporal Optogenetic Engineered MSCs for the Treatment of ConA‐Induced Liver Injury

ABSTRACT Engineered stem cells offer promise for organ regeneration but face challenges including off‐target effects and limited homing. Here, we develop a novel optogenetic strategy that spatiotemporally engineers mesenchymal stromal cells (MSCs) for liver regeneration. Through single‐cell sequencing analysis, we reveal the CXCR4/SDF1 axis as an important signaling pathway for MSC homing. By integrating the photosensitive component ultraviolet‐B resistance locus 8 (UVR8) with the homing chemokine receptor CXCR4, we construct a spatiotemporal optogenetic system for MSC transfection. Upon UV irradiation, UVR8's dissociation property is activated, enabling photosensitive proteins to migrate from the endoplasmic reticulum to the golgi apparatus and subsequently release CXCR4 on the MSC membrane. To address the limited tissue penetration of UV, we incorporate upconversion nanoparticles (UCNPs) that convert near‐infrared (NIR) light into UV. Following injection, UCNPs accumulate in the liver, where targeted NIR irradiation activates CXCR4/SDF1‐mediated MSC homing. In a ConA‐induced liver injury mouse model, the engineered MSCs regulate the SP1/SK1/S1P axis, thereby inhibiting necroptosis of intrahepatic macrophages. Moreover, hepatocyte proliferation is promoted via S1P/YAP signaling. In conclusion, our optogenetic strategy opens promising therapeutic avenues for the regeneration field and biomedical applications.