Reactive oxygen species (ROS)-mediated M1 macrophage-dependent nanomedicine remodels inflammatory microenvironment for osteoarthritis recession

Chunchun Xue; Jia Tian; Zepeng Cui; Yang Liu; Dawei Sun; Mengting Xiong; Nanxing Yi; Kaiqiang Wang; Xiaofeng Li; Yongjun Wang; Hao Xu; Weian Zhang; Qianqian Liang

doi:10.1016/j.bioactmat.2023.10.032

Reactive oxygen species (ROS)-mediated M1 macrophage-dependent nanomedicine remodels inflammatory microenvironment for osteoarthritis recession

Bioact Mater. 2023 Dec 8:33:545-561. doi: 10.1016/j.bioactmat.2023.10.032. eCollection 2024 Mar.

Authors

Chunchun Xue^{1

2

3

4}, Jia Tian⁵, Zepeng Cui⁵, Yang Liu^{1

2

3}, Dawei Sun^{1

2

3}, Mengting Xiong^{1

2

3}, Nanxing Yi^{1

2

3}, Kaiqiang Wang⁴, Xiaofeng Li⁴, Yongjun Wang^{1

2

3}, Hao Xu^{1

2

3}, Weian Zhang⁵, Qianqian Liang^{1

2

3}

Affiliations

¹ Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.
² Spine Institute, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.
³ Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
⁴ Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China.
⁵ Shanghai Key Laboratory of Functional Materials Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai, 200237, China.

Abstract

Osteoarthritis (OA) is a common chronic inflammatory disorder. Effective remodeling of inflammatory microenvironment in the joint is a promising strategy to prevent OA. However, current drugs remain unsatisfactory due to a lack of targeted and effective ways for relieving inflammatory conditions in OA joints. Bortezomib (BTZ), a proteasome inhibitor, could effectively inhibit proinflammatory cytokines but with poor accumulation in the inflammatory tissues. To overcome the shortcomings of BTZ delivery and to improve the efficacy of OA therapy, herein, we designed a novel nanomedicine (denoted as BTZ@PTK) by the co-assembly of BTZ and an amphiphilic copolymer (denoted as PTK) with ROS-cleaved thioketal (TK) linkages. The TK units in BTZ@PTK are first cleaved by the excessive ROS at OA sites, and then triggered the controlled release of BTZ, resulting in the accurate delivery and the inflammatory microenvironment remodeling. Accordingly, BTZ@PTK suppressed ROS generation and proinflammatory cytokines while promoting M1 macrophage apoptosis in lipopolysaccharide (LPS)-activated RAW264.7 macrophages or LPS/IFN-γ-treated primary macrophages, which leads to a better effect than BTZ. In OA mice, BTZ@PTK passively accumulates into inflamed joints to attenuate pain sensitivity and gait abnormality. Importantly, BTZ@PTK treatment successfully ameliorates synovitis with the reduction of synovial hyperplasia and synovitis scores by suppressing M1 macrophage polarization and promoting M1 macrophage apoptosis in the synovium, thereby delaying cartilage damage. Collectively, BTZ@PTK can effectively modulate inflammatory microenvironment for OA recession by activating M1 macrophage apoptosis and inhibiting M1macrophage-mediated inflammatory response.

Keywords: Apoptosis; Inflammatory microenvironment; Macrophages polarization; Osteoarthritis; Reactive oxygen species.