An Acid‐Neutralizing Nanoreactor Counteracts Senescence‐Driven Cartilage Degeneration in Osteoarthritis

Abstract

ABSTRACT Osteoarthritis (OA) is a multifactorial degenerative joint disease characterized by irreversible cartilage deterioration associated with chronic inflammation, oxidative stress, tissue acidosis, and abnormal mechanical loading. During OA progression, inflammation‐associated metabolic reprogramming and hypoxia‐enhanced glycolysis promote lactate accumulation and local acidosis. OA‐associated acidosis may function as an exacerbating factor within this pathological microenvironment by engaging acid‐sensing pathways and contributing to chondrocyte senescence, apoptosis, and SASP‐associated inflammatory amplification, thereby exacerbating cartilage degeneration. Accordingly, therapeutic strategies that actively neutralize pathological acidity while concurrently modulating inflammatory and oxidative stress cascades may provide a more robust, disease‐modifying approach for OA intervention. Herein, we designed a nanoreactor termed OLDH‐DP@POM by integrating mildly alkaline layered double hydroxide (LDH) nanosheets with active acid‐neutralizing capability and anchoring polyoxometalates (POM) with antioxidant activity, thereby enabling coordinated regulation of pathological acidosis and oxidative stress. Meanwhile, lubrication‐enhancing zwitterionic poly(2‐methacryloyloxyethyl phosphorylcholine) (PMPC) polymer brushes were grafted, endowing the nanoreactor with superior joint lubrication and chondroprotective capability. Both in vitro and in vivo results demonstrated that OLDH‐DP@POM effectively neutralized local acidosis at osteoarthritic lesions, substantially ameliorated synovial inflammation, suppressed Piezo‐mediated mechanotransduction, delayed chondrocyte senescence, and ultimately attenuated cartilage degeneration. Overall, this work provides a promising nanotherapeutic platform for disease‐modifying treatment of OA.