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, Y. Qi, Xiaoling Zhang, Yiyun Cheng
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. • In this study, we found senescent macrophages exist in OA synovium, which, importantly, show functional alterations such as enhanced SASP secretion, increased mitochondrial damage and impaired efferocytosis. • We for the first time constructed immuno-targeted therapy of synovial senescent macrophages for OA treatment via chloroquine-bearing polymers for delivery of superoxide dismutase. • The constructed therapy achieves therapeutic efficacy for treating not only trauma-induced OA, but aging-induced OA as well.