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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Nanodiscs: a versatile nanocarrier platform for cancer diagnosis and treatment
Cancer therapy is a significant challenge due to insufficient drug delivery to the cancer cells and non-selective killing of healthy cells by most chemotherapy agents. Nano-formulations have shown great promise for targeted drug delivery with improved efficiency. The shape and size of nanocarriers significantly affect their transport inside the body and internalization into the cancer cells. Non-spherical nanoparticles have shown prolonged blood circulation half-lives and higher cellular internalization frequency than spherical ones. Nanodiscs are desirable nano-formulations that demonstrate enhanced anisotropic character and versatile functionalization potential. Here, we review the recent development of theranostic nanodiscs for cancer mitigation ranging from traditional lipid nanodiscs encased by membrane scaffold proteins to newer nanodiscs where either the membrane scaffold proteins or the lipid bilayers themselves are replaced with their synthetic analogues. We first discuss early cancer detection enabled by nanodiscs. We then explain different strategies that have been explored to carry a wide range of payloads for chemotherapy, cancer gene therapy, and cancer vaccines. Finally, we discuss recent progress on organic–inorganic hybrid nanodiscs and polymer nanodiscs that have the potential to overcome the inherent instability problem of lipid nanodiscs.
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- Award ID(s):
- 1810767
- PAR ID:
- 10376960
- Date Published:
- Journal Name:
- Chemical Society Reviews
- Volume:
- 51
- Issue:
- 5
- ISSN:
- 0306-0012
- Page Range / eLocation ID:
- 1702 to 1728
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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