A Proton‐Activatable DNA‐Based Nanosystem Enables Co‐Delivery of CRISPR/Cas9 and DNAzyme for Combined Gene Therapy

CRISPR/Cas9 is emerging as a platform for gene therapeutics, and the treatment efficiency is expected to be enhanced by combination with other therapeutic agents. Herein, we report a proton‐activatable DNA‐based nanosystem that enables co‐delivery of Cas9/sgRNA and DNAzyme for the combined gene ther...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2022-02, Vol.61 (9), p.e202116569-n/a
Main Authors: Li, Feng, Song, Nachuan, Dong, Yuhang, Li, Shuai, Li, Linghui, Liu, Yujie, Li, Zhemian, Yang, Dayong
Format: Article
Language:English
Subjects:
Breast cancer
Chemical compounds
Cleavage
CRISPR
Deoxyribonucleic acid
DNA
DNA Nanotechnology
DNAzyme
Enzymes
Gene Editing
Gene Therapy
Nanoparticles
Pharmacology
Polymer coatings
Polymers
Protons
Rolling Circle Amplification
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Summary:CRISPR/Cas9 is emerging as a platform for gene therapeutics, and the treatment efficiency is expected to be enhanced by combination with other therapeutic agents. Herein, we report a proton‐activatable DNA‐based nanosystem that enables co‐delivery of Cas9/sgRNA and DNAzyme for the combined gene therapy of cancer. Ultra‐long ssDNA chains, which contained the recognition sequences of sgRNA in Cas9/sgRNA, DNAzyme sequence and HhaI enzyme cleavage site, were synthesized as the scaffold of the nanosystem. The DNAzyme cofactor Mn2+ was used to compress DNA chains to form nanoparticles and acid‐degradable polymer‐coated HhaI enzymes were assembled on the surface of nanoparticles. In response to protons in lysosome, the polymer coating was decomposed and HhaI enzyme was consequently exposed to recognize and cut off the cleavage sites, thus triggering the release of Cas9/sgRNA and DNAzyme to regulate gene expressions to achieve a high therapeutic efficacy of breast cancer. By programming multi‐functional sequences in one ultra‐long ssDNA chain and using it as the scaffold, we developed a lysosomal proton‐activatable DNA‐based nanosystem, which overcomes the countervailing effect of Mn2+ on Cas9 and DNAzyme, and thus achieves efficient co‐delivery of CRISPR/Cas9 and DNAzyme for combined gene therapy of breast cancer.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.202116569