A self-cascade nanoCRISPR prompts transcellular penetration to potentiate gene editing and tumor killing.
10.1016/j.apsb.2025.09.004
- Author:
Chao LIU
1
;
Yangsong XU
1
;
Ning WANG
1
;
Hongyu LIU
1
;
Xi YANG
1
;
Shiyao ZHOU
1
;
Dongxue HUANG
1
;
Yingjie LI
1
;
Yanjie YOU
2
;
Qinjie WU
1
;
Changyang GONG
1
Author Information
1. Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
2. Department of Gastroenterology, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan 750002, China.
- Publication Type:Journal Article
- Keywords:
Apoptosis;
CRISPR/Cas9;
Cancer therapy;
Delivery system;
Gene editing;
Nanoplatform;
Transcellular penetration
- From:
Acta Pharmaceutica Sinica B
2025;15(11):5933-5944
- CountryChina
- Language:English
-
Abstract:
CRISPR/Cas9-based therapeutics face significant challenges in penetrating the dense microenvironment of solid tumors, resulting in insufficient gene editing and compromised treatment efficacy. Current nanostrategies, which mainly focus on the paracellular pathway attempted to improve gene editing performance, whereas their efficiency remains uneven in the heterogenous extracellular matrix. Here, the nanoCRISPR system is prepared with self-cascading mechanisms for gene editing-mediated robust apoptosis and transcellular penetration. NanoCRISPR unlocks its self-cascade capability within the matrix metallopeptidase 2-enriched tumor microenvironment, initiating the transcellular penetration. By facilitating cellular uptake, nanoCRISPR triggers robust apoptosis in edited malignancies, promoting further transcellular penetration and amplifying gene editing in neighboring tumor cells. Benefiting from self-cascade between robust apoptosis and transcellular penetration, nanoCRISPR demonstrates continuous gene transfection/tumor killing performance (transfection/apoptosis efficiency: 1st round: 85%/84.2%; 2nd round: 48%/27%) and homogeneous penetration. In xenograft tumor-bearing mice, nanoCRISPR treatment achieves remarkable anti-tumor efficacy (∼83%) and significant survival benefits with minimal toxicity. This strategy presents a promising paradigm emphasizing transcellular penetration to enhance the effectiveness of CRISPR-based antitumor therapeutics.
