Not Only Engineering Nanomedicines, but Also Modulating the Host: The Gut Microbiome Shapes Chemotherapy Delivery to Tumors

Nanocarriers can encapsulate chemotherapy drugs in liposomes or albumin particles, but they do not necessarily deliver enough of the drug into tumors. Many particles are cleared from the bloodstream by the liver before reaching their destination. A team at The University of Texas MD Anderson Cancer Center in the United States has now found in preclinical models that this barrier depends not only on particle design but is also regulated by the gut microbiome.

The study, published in *Nature Materials*, found that after short-term use of the antibiotic metronidazole altered the gut microbiota of mice, the circulation time of nanoparticle chemotherapy drugs in the blood approximately doubled, liver clearance decreased, and more of the drug entered tumors. Researchers observed slower tumor growth and prolonged survival in models of colorectal cancer, breast cancer, melanoma, and pancreatic cancer, but the findings remain limited to animal experiments.

A key part of the mechanism lies in the liver’s Kupffer cells. These resident macrophages engulf foreign particles in the blood and are also why nanomedicines are readily intercepted. Single-cell RNA sequencing showed that after the gut microbiome was disrupted, Kupffer cells shifted from a more actively phagocytic state to a relatively quiescent one, allowing more of the drug to remain in circulation.

Metabolomic analysis further linked this change to bile acids. The production and transformation of certain bile acids depend on gut bacteria; after metronidazole reshaped the microbiome, the associated bile acid signaling decreased, and the phagocytic activity of Kupffer cells declined accordingly. This enabled the researchers to establish a pathway extending from the gut microbiome through bile acids to liver macrophages, explaining how the host alters the distribution of nanomedicines in the body.

To rule out the possibility that the drug effect was caused directly by residual antibiotics, the team transplanted the fecal microbiota of metronidazole-treated donors into germ-free mice. No drug was detected in the transplants, yet the recipients still showed lower liver clearance and greater accumulation of the drug in tumors, supporting that this characteristic can be transferred with the microbiome and further strengthening the causal relationship.

Many questions remain before clinical application. Widespread antibiotic use could disrupt the microbiome, promote antimicrobial resistance, and affect other cancer treatments; the microbiome, bile acid metabolism, and drug clearance in mice are also not equivalent to those in humans. In addition to testing short-term metronidazole combination therapy, the researchers propose reproducing the effect using specific microbial communities or approaches that modulate bile acids, and evaluating whether the microbiome and bile acids could serve as biomarkers for predicting responses to nanomedicines.