Beyond carrier design: The gut microbiota–serotonin axis modulates systemic delivery in mouse models

Efficient systemic delivery remains a major challenge for *in vivo* delivery systems (IDSs), as administered vectors are rapidly cleared by the mononuclear phagocyte system, particularly through Kupffer cell–mediated hepatic sequestration. Recent work in mouse models identifies host physiology as an important modulator of delivery efficiency, revealing that the gut microbiota influences hepatic clearance through serotonin signaling. Microbiota depletion enhanced the performance of multiple tested delivery platforms, including nanoparticles and viral vectors, leading to improved therapeutic outcomes in chemotherapy, mRNA delivery, and *in vivo* genome editing. Mechanistically, microbial sensing in the intestinal epithelium controls serotonin production from tryptophan, and circulating serotonin activates Kupffer cells through HTR2C and HTR7–ERK signaling to promote phagocytic uptake of administered carriers. This microbiota-driven gut–liver axis links microbial metabolism to host immune-mediated clearance and influences the systemic distribution of delivery systems. These findings suggest that modulation of gut microbiota or serotonin signaling may provide a host-directed approach to enhance delivery efficiency alongside conventional carrier engineering. However, the relative contribution of this pathway may vary among delivery platforms, and its generalizability, safety, and relevance to humans remain to be established.