Disrupting the Senescence-Associated Secretory Phenotype–M1Macrophage Feedback Loop in Synovitis Using Dual Nano-Switches To Restore Joint Homeostasis

Feb 4, 2026ACS nano

Stopping the harmful feedback between aging cells and inflammatory immune cells to restore joint balance in joint inflammation

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Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗

Abstract

In rat osteoarthritis models, a dual approach achieved 73.53% reduction in the synovitis index and 75.00% reduction in the OARSI score.

Osteoarthritis is a progressive condition affecting over 300 million people globally, characterized by chronic pain and functional impairment.
Synovitis, marked by inflamed synovial tissue with senescent fibroblasts and pro-inflammatory macrophages, is a key factor in osteoarthritis progression.
Senescent cells release components that promote inflammation, leading to a feedback loop that exacerbates cellular senescence.
Conventional therapies targeting either senescent cells or macrophages have limitations due to the interdependent nature of inflammation and cellular senescence.
A novel combinatorial nanomedicine platform combines synovium-targeting liposomes and M2 macrophage-derived exosomes to address both senescent cells and inflammatory macrophages.

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Osteoarthritis (OA), a leading cause of disability worldwide, impacts over 300 million people through progressive joint degeneration marked by chronic pain and functional impairment. A key driver of osteoarthritis progression is synovitis, characterized by inflamed synovial tissue harboring senescent fibroblasts and pro-inflammatory macrophages. These senescent cells secrete senescence-associated secretory phenotype (SASP) components, includining cytokines and proteases, which drive macrophage polarization toward a pro-inflammatory M1 state. Simultaneously, M1 macrophages release reactive oxygen species (ROS) and inflammatory mediators, amplifying cellular senescence and establishing a pathological feedback loop. Unfortunately, conventional single-target therapies, such as senolytics or macrophage modulators, fail to address this interdependence vicious cycle. Herein, guided by bioinformatics analysis integrated with clinical and murine specimen data, we developed an easy-to-produce combinatorial nanomedicine platform comprising: (i) synovium-targeting liposomes delivering senolytics to clear senescent fibroblasts and suppress SASP, and (ii) M2 macrophage-derived exosomes to convert M1 macrophages into regenerative M2 phenotypes. In rat OA models, this dual approach combined disrupted the senescence-inflammation cascade, achieving 73.53% synovitis index reduction and 75.00% OARSI score reduction. In summary, by concurrently clearing SASP-producing senescent cells and pro-inflammatory M1 macrophages, our strategy restores joint homeostasis and presents a translatable framework for treating age-related inflammatory disorders.