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

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.