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Theranostics 2024; 14(1):203-219. doi:10.7150/thno.88550 This issue Cite

Research Paper

Targeting DAD1 gene with CRISPR-Cas9 system transmucosally delivered by fluorinated polylysine nanoparticles for bladder cancer intravesical gene therapy

Dongdong Tang1,2,4#, Yang Yan2,5#, Yangyang Li2#, Yuqing Li3, Junqiang Tian1, Li Yang1, Hui Ding1, Ghassan Bashir3, Houhong Zhou3, Qiuxia Ding2, Ran Tao2, Shaohua Zhang2,3✉, Zhiping Wang1✉, Song Wu1,2,3✉

1. Department of Urology, Lanzhou University Second Hospital, Lanzhou 730030, China.
2. Department of Urology, The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group), Shenzhen University, Shenzhen 518000, China.
3. Department of Urology, South China Hospital, Medical School, Shenzhen University, Shenzhen 518000, China.
4. Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
5. Songshan Lake Materials Laboratory, Dongguan, 523808, China.
#These authors contributed equally to this work.

✉ Corresponding authors: wangzplzucom; wusongedu.cn; 22zshcom.

Citation:
Tang D, Yan Y, Li Y, Li Y, Tian J, Yang L, Ding H, Bashir G, Zhou H, Ding Q, Tao R, Zhang S, Wang Z, Wu S. Targeting DAD1 gene with CRISPR-Cas9 system transmucosally delivered by fluorinated polylysine nanoparticles for bladder cancer intravesical gene therapy. Theranostics 2024; 14(1):203-219. doi:10.7150/thno.88550. https://www.thno.org/v14p0203.htm
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Abstract

Graphic abstract

Background: Intravesical chemotherapy is highly recommended after transurethral resection of bladder tumor for patients with bladder cancer (BCa). However, this localized adjuvant therapy has drawbacks of causing indiscriminate damage and inability to penetrate bladder mucosal.

Methods: Fluorinated polylysine micelles (PLLF) were synthesized by reacting polylysine (PLL) with heptafluorobutyrate anhydride. Anti-apoptotic gene defender against cell death 1 (DAD1) was selected by different gene expression analysis between BCa patients and healthy individuals and identified by several biological function assays. The gene transfection ability of PLLF was verified by multiple in vitro and in vivo assays. The therapeutic efficiency of PLLF nanoparticles (NPs) targeting DAD1 were confirmed by intravesical administration using an orthotopic BCa mouse model.

Results: Decorated with fluorinated chains, PLL can self-assemble to form NPs and condense plasmids with excellent gene transfection efficiency in vitro. Loading with the CRISPR-Cas9 system designed to target DAD1 (Cas9-sgDAD1), PLLF/Cas9-sgDAD1 NPs strongly inhibited the expression of DAD1 in BCa cells and induced BCa cell apoptosis through the MAPK signaling pathway. Furthermore, intravesical administration of PLLF/Cas9-sgDAD1 NPs resulted in significant therapeutic outcomes without systemic toxicity in vivo.

Conclusion: The synthetized PLLF can transmucosally deliver the CRISPR-Cas9 system into orthotopic BCa tissues to improve intravesical instillation therapy for BCa. This work presents a new strategy for targeting DAD1 gene in the intravesical therapy for BCa with high potential for clinical applications.

Keywords: fluorinated polylysine nanoparticles, CRISPR-Cas9 system, DAD1, bladder cancer, intravesical therapy

Citation styles

APA
Tang, D., Yan, Y., Li, Y., Li, Y., Tian, J., Yang, L., Ding, H., Bashir, G., Zhou, H., Ding, Q., Tao, R., Zhang, S., Wang, Z., Wu, S. (2024). Targeting DAD1 gene with CRISPR-Cas9 system transmucosally delivered by fluorinated polylysine nanoparticles for bladder cancer intravesical gene therapy. Theranostics, 14(1), 203-219. https://doi.org/10.7150/thno.88550.

ACS
Tang, D.; Yan, Y.; Li, Y.; Li, Y.; Tian, J.; Yang, L.; Ding, H.; Bashir, G.; Zhou, H.; Ding, Q.; Tao, R.; Zhang, S.; Wang, Z.; Wu, S. Targeting DAD1 gene with CRISPR-Cas9 system transmucosally delivered by fluorinated polylysine nanoparticles for bladder cancer intravesical gene therapy. Theranostics 2024, 14 (1), 203-219. DOI: 10.7150/thno.88550.

NLM
Tang D, Yan Y, Li Y, Li Y, Tian J, Yang L, Ding H, Bashir G, Zhou H, Ding Q, Tao R, Zhang S, Wang Z, Wu S. Targeting DAD1 gene with CRISPR-Cas9 system transmucosally delivered by fluorinated polylysine nanoparticles for bladder cancer intravesical gene therapy. Theranostics 2024; 14(1):203-219. doi:10.7150/thno.88550. https://www.thno.org/v14p0203.htm

CSE
Tang D, Yan Y, Li Y, Li Y, Tian J, Yang L, Ding H, Bashir G, Zhou H, Ding Q, Tao R, Zhang S, Wang Z, Wu S. 2024. Targeting DAD1 gene with CRISPR-Cas9 system transmucosally delivered by fluorinated polylysine nanoparticles for bladder cancer intravesical gene therapy. Theranostics. 14(1):203-219.

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