Core Viewpoint - The study reveals that gut commensal bacteria are key regulators of the efficacy of in vivo delivery systems (IDS), and disrupting the gut microbiota-host interaction can significantly enhance drug and gene delivery efficiency [4][11]. Group 1: Research Findings - The research published in Science identifies that serotonin production driven by gut microbiota modulates the clearance of synthetic and viral vectors by the liver [4][5]. - By blocking serotonin signaling or through dietary interventions, the study demonstrates a significant reduction in liver clearance of IDS, leading to improved delivery efficiency [4][8]. - The enhancement in delivery efficiency results in over a threefold increase in the effectiveness of chemotherapy and oncolytic virus therapy, and a 5-15 fold increase for somatic gene editing and mRNA therapies [4][9]. Group 2: Mechanism of Action - The study uncovers a gut-liver immune axis that regulates the clearance of IDS, indicating that the long-standing challenges in drug delivery can be addressed by modulating endogenous biological pathways [5][11]. - The research highlights that the interaction between gut microbiota and liver Kupffer cells is crucial, with the gut microbiota influencing serotonin metabolism in intestinal epithelial cells, which in turn affects IDS clearance [8][9]. - The findings suggest that targeting tryptophan metabolism or serotonin signaling could provide a broadly applicable strategy to enhance IDS efficiency, reducing rapid liver clearance and hepatotoxicity [11].