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<p>The clinical efficacy of nanomedicines is often limited by hepatic sequestration, yet the endogenous programs determining this clearance state remain incompletely understood. Here we identify the gut microbiota as a regulator of nanomedicine biodistribution through bile-acid-associated programming of Kupffer cell phagocytic state. Using germ-free mice, microbial perturbation, faecal microbiota transplantation and multiomic profiling, we show that metronidazole remodels the gut microbial ecology and reprograms Kupffer cells into a reduced-uptake state, thereby suppressing hepatic clearance and enhancing the tumour accumulation of nanomedicines across multiple formulations and tumour models. Single-cell RNA sequencing reveals a shift in Kupffer cell populations from phagocytic to quiescent states, whereas metabolomic profiling identifies microbiota-dependent reductions in bile acid availability. Gut-bacteria-derived bile acids induce Kupffer cell phagocytosis, and faecal transfer transmits the low-clearance phenotype, defining a transferable gut microbiota–bile acid–Kupffer cell pathway affecting nanomedicine clearance.</p>

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A transferable gut microbiota–bile acid pathway programs nanomedicine pharmacokinetics and therapeutic response

  • 期刊论文

  • 发表日期：

    2026年7月31日

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  • Mengyu Chang,
  • Yifan Wang,
  • JongHoon Ha,
  • Zoey R. Neale,
  • Nadim J. Ajami,
  • Laurence P. Diggs,
  • Ansel P. Nalin,
  • Yifan Ma,
  • Shiyan Dong,
  • Yasmine M. Hoballah,
  • Abderrahman Day,
  • Seong Dong Jeong,
  • Annette Wu,
  • Benjamin R. Schrank,
  • Jared L. Edwards,
  • Tianyu Wang,
  • Xiaotian Wang,
  • Yen-Tzu Chang,
  • Chaoyang Tang,
  • Anthony J. Lim,
  • Michelle Najarro Torres,
  • Weiye Deng,
  • Timothy Peitsch,
  • Maurice J. Dufilho IV,
  • Sangeeta Goswami,
  • Dadi Jiang,
  • Albert C. Koong,
  • Padmanee Sharma,
  • Jennifer A. Wargo,
  • Wen Jiang,
  • Betty Y. S. Kim

摘要

The clinical efficacy of nanomedicines is often limited by hepatic sequestration, yet the endogenous programs determining this clearance state remain incompletely understood. Here we identify the gut microbiota as a regulator of nanomedicine biodistribution through bile-acid-associated programming of Kupffer cell phagocytic state. Using germ-free mice, microbial perturbation, faecal microbiota transplantation and multiomic profiling, we show that metronidazole remodels the gut microbial ecology and reprograms Kupffer cells into a reduced-uptake state, thereby suppressing hepatic clearance and enhancing the tumour accumulation of nanomedicines across multiple formulations and tumour models. Single-cell RNA sequencing reveals a shift in Kupffer cell populations from phagocytic to quiescent states, whereas metabolomic profiling identifies microbiota-dependent reductions in bile acid availability. Gut-bacteria-derived bile acids induce Kupffer cell phagocytosis, and faecal transfer transmits the low-clearance phenotype, defining a transferable gut microbiota–bile acid–Kupffer cell pathway affecting nanomedicine clearance.