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Theranostics 2023; 13(9):2774-2786. doi:10.7150/thno.81776 This issue Cite

Research Paper

Hierarchically tumor-activated nanoCRISPR-Cas13a facilitates efficient microRNA disruption for multi-pathway-mediated tumor suppression

Xiaowei Liu1†, Suleixin Yang1†, Li Wang1†, Xinyue Wu1, Xinxin Wang1, Chunqing Ou1, Jin Yang1, Linjiang Song2, Shiyao Zhou1, Qinjie Wu1✉, Changyang Gong1✉

1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, P. R. China.
2. School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, P. R. China.
† These authors contributed equally to this work.

✉ Corresponding authors: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, P. R. China. E-mail addresses: chygong14com (C Gong) and cellwqjcom (Q Wu).

Citation:
Liu X, Yang S, Wang L, Wu X, Wang X, Ou C, Yang J, Song L, Zhou S, Wu Q, Gong C. Hierarchically tumor-activated nanoCRISPR-Cas13a facilitates efficient microRNA disruption for multi-pathway-mediated tumor suppression. Theranostics 2023; 13(9):2774-2786. doi:10.7150/thno.81776. https://www.thno.org/v13p2774.htm
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Abstract

Graphic abstract

Rationale: CRISPR-Cas13a is an efficient tool for robust RNA knockdown with lower off-target effect, which may be a potentially powerful and safe tool for cancer gene therapy. However, therapeutic effect of current cancer gene therapy that targeting monogene was compromised by the multi-mutational signal pathway alterations of tumorigenesis.

Methods: Here, hierarchically tumor-activated nanoCRISPR-Cas13a (CHAIN) is fabricated for multi-pathway-mediated tumor suppression by efficient microRNA disruption in vivo. A fluorinated polyetherimide (PEI; Mw=1.8KD) with graft rate of 33% (PF33) was utilized to compact the CRISPR-Cas13a megaplasmid targeting microRNA-21 (miR-21) (pCas13a-crRNA) via self-assemble to constitute a nanoscale 'core' (PF33/pCas13a-crRNA), which was further wrapped by modified hyaluronan (HA) derivatives (galactopyranoside-PEG2000-HA, GPH) to form CHAIN.

Results: The dual-tumor-targeting and tumor-activated CHAIN not only manifested long-term circulation, but augmented tumor cellular uptake and endo/lysosomal escape, thus achieving efficient transfection of CRISPR-Cas13a megaplasmid (~ 13 kb) in tumor cells with minimal toxity. Efficient knockdown of miR-21 by CHAIN restored programmed cell death protein 4 (PDCD4) and reversion‐inducing‐cysteine‐rich protein with Kazal motifs (RECK) and further crippled downstream matrix metalloproteinases-2 (MMP-2), which undermined cancer proliferation, migration and invasion. Meanwhile, the miR-21-PDCD4-AP-1 positive feedback loop further functioned as an enhanced force for anti-tumor activity.

Conclusion: Treatment with CHAIN in hepatocellular carcinoma mouse model achieved significant inhibition of miR-21 expression and rescued multi-pathway, which triggered substantial tumor growth suppression. By efficient CRISPR-Cas13a induced interference of one oncogenic microRNA, the CHAIN platform exerted promising capabilities in cancer treatment.

Keywords: tumor-activated, CRISPR-Cas13a, microRNA disruption, multi-pathway regulation, cancer treatment

Citation styles

APA
Liu, X., Yang, S., Wang, L., Wu, X., Wang, X., Ou, C., Yang, J., Song, L., Zhou, S., Wu, Q., Gong, C. (2023). Hierarchically tumor-activated nanoCRISPR-Cas13a facilitates efficient microRNA disruption for multi-pathway-mediated tumor suppression. Theranostics, 13(9), 2774-2786. https://doi.org/10.7150/thno.81776.

ACS
Liu, X.; Yang, S.; Wang, L.; Wu, X.; Wang, X.; Ou, C.; Yang, J.; Song, L.; Zhou, S.; Wu, Q.; Gong, C. Hierarchically tumor-activated nanoCRISPR-Cas13a facilitates efficient microRNA disruption for multi-pathway-mediated tumor suppression. Theranostics 2023, 13 (9), 2774-2786. DOI: 10.7150/thno.81776.

NLM
Liu X, Yang S, Wang L, Wu X, Wang X, Ou C, Yang J, Song L, Zhou S, Wu Q, Gong C. Hierarchically tumor-activated nanoCRISPR-Cas13a facilitates efficient microRNA disruption for multi-pathway-mediated tumor suppression. Theranostics 2023; 13(9):2774-2786. doi:10.7150/thno.81776. https://www.thno.org/v13p2774.htm

CSE
Liu X, Yang S, Wang L, Wu X, Wang X, Ou C, Yang J, Song L, Zhou S, Wu Q, Gong C. 2023. Hierarchically tumor-activated nanoCRISPR-Cas13a facilitates efficient microRNA disruption for multi-pathway-mediated tumor suppression. Theranostics. 13(9):2774-2786.

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