An Acid-Neutralizing Nanoreactor Counteracts Senescence-Driven Cartilage Degeneration in Osteoarthritis.

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.