Sequential Targeting Chondroitin Sulfate-Bilirubin Nanomedicine Attenuates Osteoarthritis via Reprogramming Lipid Metabolism in M1 Macrophages

Caifeng Deng; Yongbing Xiao; Xuan Zhao; Hui Li; Yuxiao Chen; Kelong Ai; Ting Jiang; Jie Wei; Xiaoyuan Chen; Guanghua Lei; Chao Zeng

doi:10.1002/advs.202411911

Sequential Targeting Chondroitin Sulfate-Bilirubin Nanomedicine Attenuates Osteoarthritis via Reprogramming Lipid Metabolism in M1 Macrophages

Adv Sci (Weinh). 2025 Jan 10:e2411911. doi: 10.1002/advs.202411911. Online ahead of print.

Authors

Caifeng Deng^{1

2

3}, Yongbing Xiao^{1

2

3}, Xuan Zhao^{1

2

3}, Hui Li^{1

2

3}, Yuxiao Chen^{1

2

3}, Kelong Ai⁴, Ting Jiang^{1

2

3}, Jie Wei^{1

2

3}, Xiaoyuan Chen^{5

6

7}, Guanghua Lei^{1

2

3

8}, Chao Zeng^{1

2

3

8}

Affiliations

¹ Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
² Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
³ Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
⁴ Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, 410008, China.
⁵ Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, 119074, Singapore.
⁶ Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore.
⁷ Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore.
⁸ National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.

PMID: 39792653
DOI: 10.1002/advs.202411911

Abstract

The infiltration and excessive polarization of M1 macrophages contribute to the induction and persistence of low-grade inflammation in joint-related degenerative diseases such as osteoarthritis (OA). The lipid metabolism dysregulation promotes M1 macrophage polarization by coordinating the compensatory pathways of the inflammatory and oxidative stress responses. Here, a self-assembling, licofelone-loaded nanoparticle (termed LCF-CSBN), comprising chondroitin sulfate and bilirubin joined by an ethylenediamine linker, is developed to selectively reprogram lipid metabolism in macrophage activation. LCF-CSBN is internalized by M1 macrophages via CD44-mediated endocytosis and targets the Golgi apparatus accompanied with the reactive oxygen species-responsive release of licofelone (LCF, dual inhibitor of arachidonic acid metabolism). LCF-CSBN effectively promotes M1 to M2 macrophage transition by reprogramming the Golgi apparatus-related sphingolipid metabolism and arachidonic acid metabolism. Intra-articularly injected LCF-CSBN retains in the joint for up to 28 days and accumulates into M1 macrophages. Moreover, LCF-CSBN can effectively attenuate joint inflammation, oxidative stress, and cartilage degeneration in OA model rats. These findings indicate the promising potential of lipid-metabolism-reprogramming LCF-CSBN in the targeted therapy of OA.

Keywords: M1 macrophages repolarization; nanoparticles; osteoarthritis; reprogramming of lipid metabolism; targeted therapy.

Abstract

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