Transcriptomic analysis of macrophages

Here, we identify the gut microbiota as a central determinant of nanomedicine biodistribution, acting through transcriptional programming of liver-resident macrophages rather than modulation of adaptive immunity. Using germ-free mice, fecal microbiota transplantation, and targeted microbial perturbation, we show that the nitroimidazole antibiotic metronidazole reconfigures gut microbial ecology and reprograms Kupffer cells into a reduced-uptake state.

This shift suppresses hepatic sequestration and enhances tumour accumulation of clinically deployed nanomedicines across multiple cancer models and nanoparticle formulations. Single-cell RNA sequencing reveals a coordinated downregulation of phagocytic and scavenger receptor pathways in Kupffer cells, while metabolomic profiling identifies microbiota-dependent changes in bile acid availability. Restoration of this altered microbial state through fecal transfer is sufficient to transmit the low-clearance phenotype, demonstrating causal and transferable host control of nanomedicine fate.