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.

Biological functions of supramolecular assemblies of small molecules in the cellular environment

“…Such inhibition of mitochondrial protein synthesis sensitizes the cancer cells to cisplatin. 71 This intriguing phenomenon expands the applications of SASMs to repurpose clinically validated drugs for effectively suppressing cancer cells and reducing the systemic burden.…”

Smart Nanogatekeepers for Tumor Theranostics

“…[71] Tumor cells exploit oxidative phosphorylation and respiration to support their excessive proliferation, tumorigenesis, and chemotherapeutic resistance. [72] Considering the vital function of mitochondria and the advantages of morphology transformation strategies, certain perimitochondrial or intramitochondrial structure-transformable nanoplatforms have been engineered for potential tumor theranostics. Xu and co-workers designed a peptide-lipid conjugate (Flag-(C16) 2 ) composed of enterokinase (ENTK)-cleavable Flagtag (DYKDDDDK) 64 , and lipid-like (NH 2 -E-(C16) 2 ), which selfassembles into micelles in aqueous environments.…”

Biomaterials based on noncovalent interactions of small molecules

“…Owing to the precise spatiotemporal control of EISA, targeting subcellular organelles or subcellular proteins with EISA is an emerging field in cancer therapy (Feng et al, 2018[ 22 ]; He et al, 2018[ 36 ], 2020[ 33 ]). Integrating extracellular EISA with the mitochondrial targeting ability of triphenyl phosphonium, the peptide derivative ( 11 ) induce mitochondrial dysfunction and the release of cytochrome c, therefore killing the cancer cells (Figure 3C (Fig.…”

“…3) ) (Wang et al, 2016[ 82 ]). Incorporating ENTK to induce perimitochondrial self-assembly directly delivers chloramphenicol (CLRP) into mitochondria, selectively sensitizing and killing cancer cells (He et al, 2020[ 33 ]). A phosphopeptide bearing AVPI segment, which is the antagonistic motif to the inhibitors of apoptotic proteins (IAPs), sequestrates IAPs and selectively induce apoptosis of cancer cells (He et al, 2020[ 34 ]).…”