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

Oct 2, 2025Bioactive materials

Changing old immune cells in joint lining may ease joint damage from injury and aging

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Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗

Abstract

Intraarticular injection of pCQ/SOD nanoparticles in mice successfully alleviates trauma-induced and aging-induced osteoarthritis.

Single-cell sequencing shows increased senescent macrophages in trauma-induced osteoarthritis compared to controls.
Senescent macrophages exhibit enhanced inflammatory characteristics, mitochondrial damage, and impaired clearance of dead cells.
A novel nanoparticle, pCQ/SOD, effectively delivers superoxide dismutase to synovial macrophages.
pCQ/SOD inhibits macrophage senescence through specific cellular signaling pathways, promoting a shift from inflammatory to reparative macrophage states.
The nanoparticles reduce mitochondrial damage and associated inflammatory signals in the joint environment.

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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.

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

Abstract

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