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Since mitochondria contribute to tumorigenesis and drug resistance in cancer, mitochondrial genetic engineering promises a new direction for cancer therapy. Here, we report the use of the perimitochondrial enzymatic noncovalent synthesis (ENS) of peptides for delivering genes selectively into the mitochondria of cancer cells for mitochondrial genetic engineering. Specifically, the micelles of peptides bind to the voltage-dependent anion channel (VDAC) on mitochondria for the proteolysis by enterokinase (ENTK), generating perimitochondrial nanofibers in cancer cells. This process, facilitating selective delivery of nucleic acid or gene vectors into mitochondria of cancer cells, enables the mitochondrial transgene expression of CRISPR/Cas9, FUNDC1, p53, and fluorescent proteins. Mechanistic investigation indicates that the interaction of the peptide assemblies with the VDAC and mitochondrial membrane potential are necessary for mitochondria targeting. This local enzymatic control of intermolecular noncovalent interactions enables selective mitochondrial genetic engineering, thus providing a strategy for targeting cancer cells.
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Enzymatic Delivery of Magnetic Nanoparticles into Mitochondria of Live Cells
Abstract Delivering magnetic nanoparticles (MNPs) into mitochondria provides a facile approach to manipulate cell life because mitochondria play essential roles in cell survival and death. Here we report the use of enzyme‐responsive peptide assemblies to deliver MNPs into mitochondria of live cells. The mitochondria‐targeting peptide (Mito‐Flag), as the substrate of enterokinase (ENTK), assembles with MNPs in solution. The MNPs that are encapsulated by Mito‐Flag peptides selectively accumulate to the mitochondria of cancer cells, rather than normal cells. The mitochondrial localization of MNPs reduces the viability of the cancer cells, but hardly affects the survival of the normal cell. This work demonstrates a new and facile strategy to specifically transport MNPs to the mitochondria in cancer cells for exploring the applications of MNPs as the targeted drug for biomedicine and cancer therapy.
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- Award ID(s):
- 2011846
- PAR ID:
- 10267331
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- ChemNanoMat
- Volume:
- 7
- Issue:
- 10
- ISSN:
- 2199-692X
- Format(s):
- Medium: X Size: p. 1104-1107
- Size(s):
- p. 1104-1107
- Sponsoring Org:
- National Science Foundation
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