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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.
Abstract:
The development of human microbiome has collectively correlated the sophisticated interactions between Fusobacterium nucleatum and colorectal cancers (CRCs). However, the treatment of CRC via disruption of gastrointestinal flora remains less explored. Aiming at the up-regulated activity of nitroreductase in F. nucleatum-infected tumors, here, we developed the nitroreductase-instructed supramolecular self-assembly. The designed assembly precursors underwent enzymatic transformation to form assemblies, which agglutinated F. nucleatum and eradicated the targeted bacteria. These assemblies with anti-F. nucleatum activity could further alleviate the bacteria-induced drug resistance effect, thus sensitizing CRC cells against chemo-drugs. Eventually, in mice bearing F. nucleatum-infected CRC, the local introduction of nitroreductase-instructed assemblies could efficiently inhibit the tumor growth. Overall, this study incorporated nitroreductase to broaden the toolbox of enzyme-instructed supramolecular self-assembly. The local introduction of nitroreductase-instructed assemblies could target F. nucleatum to eliminate its contribution to CRC drug resistance and ameliorate chemotherapy outcomes.
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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