A Decoy‐Receptor‐Armed Biomimetic Nanotherapeutic With Inherent Tropism for Conserved Pathogenic Macrophages for Treating Osteoarthritis and Intervertebral Disc Degeneration

ABSTRACT Osteoarthritis (OA) and intervertebral disc degeneration (IVDD) are debilitating musculoskeletal disorders driven by shared inflammatory pathologies, yet lack effective disease‐modifying therapies. Pro‐inflammatory macrophages are central to their pathogenesis, but their selective therapeutic modulation remains a major challenge. Here, we first used single‐cell transcriptomics to identify a conserved, pathogenic interleukin‐1β (IL‐1β) + macrophage signature fueled by a shared nuclear factor‐κB (NF‐κB)‐inflammation axis in human OA and IVDD. We engineered a macrophage‐biomimetic nanosystem (GM1‐dMOF@PTL), a “doppelgänger” nanosystem designed for targeted cellular reprogramming. The platform consists of a Parthenolide (PTL)‐loaded, lysosome‐escaping metal–organic framework (MOF) core camouflaged with inflammatory macrophage membranes, with the IL‐1β decoy receptor, interleukin‐1 receptor type 2 (IL‐1R2), overexpressed. This design enables a multi‐pronged immunomodulatory strategy: the decoy receptor could neutralize extracellular IL‐1β, while the macrophage‐biomimetic surface facilitates homotypic targeting and preferential uptake by inflammatory macrophages. Upon internalization, the nanosystem potently suppresses the NF‐κB/ NLR family pyrin domain containing 3 (N inflammasome axis, effectively disarming the cell's pyroptotic program. Crucially, local administration in mouse models preserved disc and cartilage integrity, resolved inflammation, and provided sustained alleviation of pain hypersensitivity. This study presents a unified, disease‐modifying nanotherapeutic strategy that targets a shared cellular driver by synergistically neutralizing inflammatory signals and reprogramming pathogenic immune cells to attenuate both spine and joint degeneration.