Commensal-driven serotonin production modulates in vivo delivery of synthetic and viral vectors
Summary
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. Tran
Content
# Commensal-driven serotonin production modulates in vivo delivery of synthetic and viral vectors
*Published: 2026 Mar 19*
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.
DOI: 10.1126/science.adu7686