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Title: Enzymatic Noncovalent Synthesis for Mitochondrial Genetic Engineering of Cancer Cells
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.  more » « less
Award ID(s):
2011846
PAR ID:
10506762
Author(s) / Creator(s):
; ; ; ; ; ; ;
Publisher / Repository:
Cell Press
Date Published:
Journal Name:
Cell Reports Physical Science
Volume:
1
Issue:
12
ISSN:
2666-3864
Page Range / eLocation ID:
100270
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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