Commensal-driven serotonin production modulates in vivo delivery of synthetic and viral vectors

  • Science. 2026 Mar 19;391(6791):eadu7686. doi: 10.1126/science.adu7686.
Qin Wang  #  1 ,  Ziqi Chen  #  1 ,  Guorong Zhang  #  1 ,  Jiale Yang  1 ,  Runfan Hu  1 ,  Tongyue Yao  1 ,  Cici Zeng  1  2 ,  Shugeng Zhang  3 ,  Wei Jiang  1  4  5 ,  Shu Zhu  1  2 ,  Yucai Wang  1  2  4  5
Affiliations
  • 1. State Key Laboratory of Immune Response and Immunotherapy, Department of Radiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  • 2. Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China.
  • 3. Department of Organ Transplantation Center, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  • 4. Suzhou Institute for Advanced Research, University of Science and Technology of China, Suzhou, China.
  • 5. State Key Laboratory of Precision and Intelligent Chemistry, Department of Polymer Science and Engineering, School of Chemistry and Materials Science, University of Science and Technology of China, Hefei, China.
  • # Contributed equally.
PMID: 41855345 DOI: 10.1126/science.adu7686
Abstract

In vivo delivery systems (IDSs) are designed to protect and transport therapeutics, but their clinical applications are hindered by low delivery efficiency. We identified gut microbiota as key regulators of efficacy of IDS-based therapies and that disrupting commensal-host interactions markedly improves drug and gene delivery. Intestinal epithelial cells sense microbial stimulation and remotely activate Kupffer cells through serotonin production, thereby driving hepatic IDS clearance. Transient suppression of serotonin signaling, through receptor blockade or dietary intervention, mitigates hepatic IDS clearance and improves delivery efficiency. This strategy yielded more than threefold therapeutic enhancement in chemotherapy and oncolytic virotherapy and 5- to 15-fold improvements in somatic genome editing and messenger RNA-based therapies. These findings reveal a gut-liver immune axis that can be therapeutically exploited to improve IDS-based Cancer and gene therapies.

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