Nanoengineered cargo with targeted in vivo Foxo3 gene editing modulated mitophagy of chondrocytes to alleviate osteoarthritis.
10.1016/j.apsb.2024.12.008
- Author:
Manyu CHEN
1
;
Yuan LIU
2
;
Quanying LIU
3
;
Siyan DENG
1
;
Yuhan LIU
4
;
Jiehao CHEN
5
;
Yaojia ZHOU
6
;
Xiaolin CUI
6
;
Jie LIANG
1
;
Xingdong ZHANG
1
;
Yujiang FAN
1
;
Qiguang WANG
1
;
Bin SHEN
2
Author Information
1. National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, China.
2. Orthopedics Research Institute, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu 610041, China.
3. Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University (Army Medical University), Chongqing 400038, China.
4. The Third Affiliated Hospital of Jinzhou Medical University, Jinzhou 121000, China.
5. Animal Laboratory Center of West China Hospital, West China Hospital, Sichuan University, Chengdu 610041, China.
6. Christchurch Regenerative Medicine and Tissue Engineering (CReaTE) Group, School of Medicine, the Chinese University of Hong Kong, Shenzhen 518172, China.
- Publication Type:Journal Article
- Keywords:
CRISPR/Cas9 gene editing;
Cartilage regeneration;
Injectable hydrogel microspheres;
In vivo Foxo3 gene editing;
Mitophagy;
Nanoengineered cargo;
Osteoarthritis;
PINK1/Parkin pathway
- From:
Acta Pharmaceutica Sinica B
2025;15(1):571-591
- CountryChina
- Language:English
-
Abstract:
Mitochondrial dysfunction in chondrocytes is a key pathogenic factor in osteoarthritis (OA), but directly modulating mitochondria in vivo remains a significant challenge. This study is the first to verify a correlation between mitochondrial dysfunction and the downregulation of the FOXO3 gene in the cartilage of OA patients, highlighting the potential for regulating mitophagy via FOXO3 gene modulation to alleviate OA. Consequently, we developed a chondrocyte-targeting CRISPR/Cas9-based FOXO3 gene-editing tool (FoxO3) and integrated it within a nanoengineered 'truck' (NETT, FoxO3-NETT). This was further encapsulated in injectable hydrogel microspheres (FoxO3-NETT@SMs) to harness the antioxidant properties of sodium alginate and the enhanced lubrication of hybrid exosomes. Collectively, these FoxO3-NETT@SMs successfully activate mitophagy and rebalance mitochondrial function in OA chondrocytes through the Foxo3 gene-modulated PINK1/Parkin pathway. As a result, FoxO3-NETT@SMs stimulate chondrocytes proliferation, migration, and ECM production in vitro, and effectively alleviate OA progression in vivo, demonstrating significant potential for clinical applications.
