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Here, we develop a novel optogenetic strategy that spatiotemporally engineers mesenchymal stromal cells (MSCs) for liver regeneration. Through single\u2010cell sequencing analysis, we reveal the CXCR4\/SDF1 axis as an important signaling pathway for MSC homing. By integrating the photosensitive component ultraviolet\u2010B 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\u2010infrared (NIR) light into UV. Following injection, UCNPs accumulate in the liver, where targeted NIR irradiation activates CXCR4\/SDF1\u2010mediated MSC homing. In a ConA\u2010induced 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.<\/jats:p>","DOI":"10.1002\/adma.74954","type":"journal-article","created":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T05:32:31Z","timestamp":1789191151000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Spatiotemporal Optogenetic Engineered MSCs for the Treatment of ConA\u2010Induced Liver Injury"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-8610-2152","authenticated-orcid":false,"given":"Ran","family":"An","sequence":"first","affiliation":[{"name":"Division of Hepatobiliary and Transplantation Surgery Department of General Surgery Nanjing Drum Tower Hospital the Affiliated Hospital of Medical School Nanjing University  Nanjing 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4349-750X","authenticated-orcid":false,"given":"Jinglin","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Hepatobiliary and Transplantation Surgery Department of General Surgery Nanjing Drum Tower Hospital the Affiliated Hospital of Medical School Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6198-2904","authenticated-orcid":false,"given":"Haozhen","family":"Ren","sequence":"additional","affiliation":[{"name":"Division of Hepatobiliary and Transplantation Surgery Department of General Surgery Nanjing Drum Tower Hospital the Affiliated Hospital of Medical School Nanjing University  Nanjing 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