Nitroreductase-instructed supramolecular assemblies for microbiome regulation to enhance colorectal cancer treatments

Jiali Chen1,2, Pai Zhang1,3, Yan Zhao1,2

  • 1CAS Center for Excellence in Nanoscience, CAS Key Laboratory of Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing 100190, China.

Science Advances
|November 9, 2022
PubMed

Insights

This study introduces a novel nitroreductase-instructed supramolecular self-assembly to target Fusobacterium nucleatum in colorectal cancer (CRC). This approach eradicates bacteria, overcomes drug resistance, and inhibits tumor growth in preclinical models.

Area of Science:

  • Biochemistry
  • Microbiology
  • Nanotechnology

Background:

  • The human microbiome, particularly Fusobacterium nucleatum, plays a significant role in colorectal cancer (CRC) development.
  • Targeting gastrointestinal flora for CRC treatment is an underexplored therapeutic avenue.
  • Fusobacterium nucleatum exhibits upregulated nitroreductase activity in infected tumors.

Purpose of the Study:

  • To develop a novel therapeutic strategy targeting Fusobacterium nucleatum in CRC.
  • To leverage nitroreductase activity for precise drug delivery and bacterial eradication.
  • To overcome F. nucleatum-induced chemoresistance and improve treatment outcomes.

Main Methods:

  • Design and synthesis of nitroreductase-instructed supramolecular self-assembly precursors.
  • Enzymatic transformation of precursors into self-assembled structures within tumors.
  • In vitro and in vivo evaluation of anti-F. nucleatum activity and CRC cell sensitization.
  • Assessment of tumor growth inhibition in a mouse model of F. nucleatum-infected CRC.

Main Results:

  • The developed assemblies effectively agglutinated and eradicated Fusobacterium nucleatum.
  • The assemblies sensitized colorectal cancer cells to chemotherapy by alleviating drug resistance.
  • Local administration of the assemblies significantly inhibited tumor growth in a preclinical CRC model.
  • The study demonstrated the successful incorporation of nitroreductase into enzyme-instructed supramolecular self-assembly.

Conclusions:

  • Nitroreductase-instructed supramolecular self-assembly offers a promising strategy for targeting Fusobacterium nucleatum in CRC.
  • This approach can effectively eliminate bacteria, overcome drug resistance, and enhance chemotherapy efficacy.
  • The findings broaden the application of enzyme-instructed supramolecular self-assembly in cancer therapy.

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