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Perimitochondrial Enzymatic Self-Assembly for Selective Targeting the Mitochondria of Cancer Cells.

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.

SUBMITTER: He H

PROVIDER: S-EPMC7316614 | biostudies-literature |

REPOSITORIES: biostudies-literature

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