Xiangbo Zeng,1,2,* Dingrui Nie,1,3,* Zhen Liu,2 Xueting Peng,1 Xianfeng Wang,1 Kangjie Qiu,1 Shuxin Zhong,1 Ziwei Liao,4 Xianfeng Zha,1,5 Yangqiu Li,1,2 Chengwu Zeng1 

1Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, 510632, People’s Republic of China; 2Department of Hematology, First Affiliated Hospital, Jinan University, Guangzhou, 510632, People’s Republic of China; 3Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People’s Republic of China; 4Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, 510180, People’s Republic of China; 5Department of Clinical Laboratory, First Affiliated Hospital, Jinan University, Guangzhou, 510632, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Yangqiu Li; Chengwu Zeng, Jinan University, No. 601, West Huangpu Avenue, Guangzhou, Guangdong, People’s Republic of China, Email yangqiuli@hotmail.com; bio-zcw@163.com

Introduction: T-cell acute lymphoblastic leukemia (T-ALL) is a malignant hematological disease with limited targeted therapy options. Overexpression of B-cell lymphoma/leukemia 11B is frequently observed in T-ALL and contributes to leukemogenesis. Knockdown of BCL11B inhibits T-ALL cell proliferation and induces apoptosis, making it a potential therapeutic target. However, the clinical application of siRNA therapies is hindered by challenges such as poor delivery efficiency and limited clinical outcomes.
Methods: We developed a targeted delivery system for BCL11B siRNA (siBCL11B) using generation 5 polyamidoamine (G5-PAMAM) dendrimers conjugated with the sgc8 aptamer, which specifically binds to the T-ALL cell membrane protein PTK7. This nanoparticle, designated G5-sgc8-siBCL11B, was designed to selectively deliver siRNA to T-ALL cells. In vitro and in vivo experiments were conducted to evaluate its therapeutic efficacy and safety.
Results: We demonstrate that sgc8-conjugated siBCL11B nanoparticles selectively and efficiently target BCL11B-overexpressing T-ALL cells, significantly inhibiting cell viability and promoting apoptosis while exhibiting minimal impact on the viability of normal T cells. In T-ALL mouse model studies, G5-sgc8-siBCL11B and G5-siBCL11B significantly inhibited the progression of T-ALL in vivo, extending the survival of mice compared to the control (CTR), G5, and G5-sgc8 groups. Although there was no significant difference in survival between the G5-sgc8-siBCL11B and G5-siBCL11B groups, a trend towards improved survival was observed (p = 0.0993).
Conclusion: The G5-sgc8-siBCL11B nanoparticle system demonstrated efficient delivery and significant therapeutic efficacy, highlighting its potential as a promising novel approach for the treatment of T-ALL.

Keywords: BCL11B, T-ALL, aptamer, sgc8, siBCL11B, PAMAM