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Updated: Dec 22, 2025
Author Spotlight: Transmitochondrial Cybrid Generation Using Cancer Cell Lines
Published on: March 17, 2023
Perimitochondrial Enzymatic Self-Assembly for Selective Targeting the Mitochondria of Cancer Cells
Hongjian He1, Xinyi Lin1, Jiaqi Guo1
1Department of Chemistry, Brandeis University, 415 South Street, Waltham, Massachusetts 02453, United States.
Abstract:
Emerging evidence indicates that mitochondria contribute to drug resistance in cancer, but how to selectively target the mitochondria of cancer cells remains less explored. Here, we show perimitochondrial enzymatic self-assembly for selectively targeting the mitochondria of liver cancer cells. Nanoparticles of a peptide-lipid conjugate, being a substrate of enterokinase (ENTK), encapsulate chloramphenicol (CLRP), a clinically used antibiotic that is deactivated by glucuronidases in cytosol but not in mitochondria. Perimitochondrial ENTK cleaves the Flag-tag on the conjugate to deliver CLRP selectively into the mitochondria of cancer cells, thus inhibiting the mitochondrial protein synthesis, inducing the release of cytochrome c into the cytosol and resulting in cancer cell death. This strategy selectively targets liver cancer cells over normal liver cells. Moreover, blocking the mitochondrial protein synthesis sensitizes the cancer cells, relying on glycolysis and/or OXPHOS, to cisplatin. This work illustrates a facile approach, selectively targeting mitochondria of cancer cells and repurposing clinically approved ribosome inhibitors, to interrupt the metabolism of cancer cells for cancer treatment.
Insights
Scientists developed a new method to target cancer cell mitochondria using self-assembling nanoparticles. This approach delivers drugs specifically to liver cancer mitochondria, inhibiting protein synthesis and causing cancer cell death.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Mitochondria play a role in cancer drug resistance.
- Selective targeting of cancer cell mitochondria is an underexplored area.
- Developing strategies to overcome mitochondrial drug resistance is crucial for effective cancer therapy.
Purpose of the Study:
- To develop a method for selective mitochondrial targeting in liver cancer cells.
- To investigate the potential of perimitochondrial enzymatic self-assembly for drug delivery.
- To explore the repurposing of clinically approved drugs for enhanced cancer treatment.
Main Methods:
- Utilized peptide-lipid conjugate nanoparticles as a substrate for enterokinase (ENTK).
- Encapsulated chloramphenicol (CLRP), an antibiotic deactivated in the cytosol but stable in mitochondria.
- Leveraged perimitochondrial ENTK activity to cleave a Flag-tag, enabling selective CLRP delivery into mitochondria.
Main Results:
- Achieved selective delivery of CLRP into the mitochondria of liver cancer cells.
- Demonstrated inhibition of mitochondrial protein synthesis and induction of cytochrome c release.
- Showcased selective targeting of cancer cells over normal liver cells.
- Confirmed that blocking mitochondrial protein synthesis sensitizes cancer cells to cisplatin.
Conclusions:
- Perimitochondrial enzymatic self-assembly offers a facile approach for selective mitochondrial targeting in cancer.
- Repurposing ribosome inhibitors can disrupt cancer cell metabolism for therapeutic benefit.
- This strategy holds promise for developing novel liver cancer treatments by targeting mitochondrial function.
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