Supramolecular Nanogel‐Enabled pH‐Mediated Lubrication Mode Transition for Modulating Inflammatory Microenvironment in Osteoarthritis Therapy

ABSTRACT Elevated interfacial friction and acidified microenvironments in osteoarthritis (OA) drive coupled mechanical–biological failure, destabilizing lubrication and amplifying cellular stress, thereby accelerating cartilage degeneration and limiting therapeutic efficacy. Here, we report pH‐responsive supramolecular nanogels (NGs) composed of benzimidazole‐modified polyethylene glycol (PEG‐BM) and β‐cyclodextrin‐modified hyaluronic acid (HA‐CD) that undergo a microenvironment‐triggered lubrication‐regime transition. Surface force apparatus measurements directly revealed a transition from interfacial sliding under physiological conditions to rolling‐assisted lubrication under acidic conditions, accompanied by nanoscale interfacial structures consistent with a rolling‐bearing‐like mechanism. All‐atom molecular dynamics simulations identified protonation‐induced weakening of the β‐CD/BM host–guest motif and enhanced guest hydration as molecular drivers of pH‐triggered supramolecular reconstruction, providing a molecular basis for the adaptive interfacial transition. Comparative transcriptomic analysis showed that dexamethasone‐loaded NGs (NGD) were associated with ECM–receptor interaction, focal adhesion, integrin‐mediated adhesion, actin‐cytoskeletal organization and mechanosensitive cellular responses. In vivo, drug‐free NGs achieved therapeutic outcomes comparable to NGD. Mechanistically, protonation‐driven host–guest reconstruction enables pH‐adaptive lubrication, which is associated with matrix‐interactive and mechanosensitive cellular programs favorable for matrix homeostasis and tissue preservation. These findings establish a multiscale mechanobiological framework linking molecular reconstruction, adaptive interfacial lubrication and matrix‐preserving biological remodeling, providing a strategy for microenvironment‐responsive mechanical regulation in OA therapy.