Remodeling of senescent macrophages in synovium alleviates trauma- and aging-induced osteoarthritis

Yuhang Liu; Jianan Duan; Yifan Dang; Ruihan Hao; Hui Wang; Echuan Tan; Ruijue Wang; Yuhan Li; Song Zhang; Yuanchi Wang; Jia Lv; Yuxin Qi; Xiaoling Zhang; Yiyun Cheng

doi:10.1016/j.bioactmat.2025.09.016

Remodeling of senescent macrophages in synovium alleviates trauma- and aging-induced osteoarthritis

Bioact Mater. 2025 Sep 16:55:42-56. doi: 10.1016/j.bioactmat.2025.09.016. eCollection 2026 Jan.

Authors

Yuhang Liu¹, Jianan Duan^{2

3}, Yifan Dang^{4

5}, Ruihan Hao¹, Hui Wang³, Echuan Tan², Ruijue Wang³, Yuhan Li², Song Zhang³, Yuanchi Wang², Jia Lv², Yuxin Qi^{4

5}, Xiaoling Zhang^{4

5}, Yiyun Cheng²

Affiliations

¹ Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Rd, Shanghai, 200233, China.
² Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, 200241, China.
³ South China Advanced Institute for Soft Matter Science and Technology, School of Emergent Soft Matter, South China University of Technology, Guangzhou, 510640, China.
⁴ Department of Orthopedic Surgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, 200092, China.
⁵ National Facility for Translational Medicine, Shanghai, 200240, China.

Abstract

Osteoarthritis (OA) is one of the most concerned aging-related diseases in the worldwide, yet the investigation of immune senescence in joint and related therapies are still poorly identified. Single-cell sequencing analysis and immunofluorescence of OA synovium reveal increased senescent macrophages in trauma-induced OA compared to controls. Importantly, senescent macrophages in OA synovium showed enhanced M1 polarization, mitochondrial damage and impaired efferocytosis, which could lead to increased senescence-associated secretory phenotypes (SASPs) in the joint and further exacerbate OA. Hence, a novel senotherapeutic nanoparticle is developed using chloroquine (CQ)-bearing polymers (pCQ) for targeted delivery of superoxide dismutase (SOD) to synovial macrophages, termed as pCQ/SOD. The nanoparticle achieves efficient intracellular delivery of SOD to synovial macrophages. RNA-seq results reveal that pCQ/SOD nanoparticle inhibits macrophage senescence via p53 and cellular senescence signaling pathway, further reprograms M1-to-M2 repolarization. Furthermore, the delivered SOD inhibits BAX-dependent mitochondrial outer membrane permeabilization (MOMP) which further reduces mitochondrial DNA (mtDNA) release and SASP secretion, while pCQ promotes macrophage efferocytosis against apoptotic cells via STAT3/ADAM17/MerTK signaling. As a result, intraarticular injection of pCQ/SOD nanoparticles in mice successfully alleviates not only trauma-induced OA, but aging-induced OA as well. The developed senotherapeutic nanoparticle in this study offers an effective approach for remodeling of senescent macrophages in synovium and a promising therapeutic strategy for OA treatment.

Keywords: Efferocytosis; Intracellular protein delivery; Osteoarthritis; Polymer nanoparticle; Senescence.