Six in One: 6S‐NP Supramolecular Nanoparticles for Super‐Lubrication, Inflammation Suppression, and Senescence Reversal in Mechanically Aggravated Joint Disorders

Mechanical overload and oxidative inflammation jointly drive the progression of friction-induced, age-related joint degeneration. Current clinically employed viscosupplementation strategies, such as hyaluronic acid, only offer transient lubrication, and under high-shear conditions, it undergoes rapid viscoelasticity deterioration, greatly limiting lubrication property. Here, we reported a multifunctional nanoplatform system (6S-NP), which integrated stimuli-responsive, self-renewable, supramolecular-synergistic, super-lubricating, sustained-retaining, and senescence-reversible features for achieving adaptive treatment in mechanically aggravated age-related joint disorders. Under shear, the host-guest bonds partially dissociated, which released and redistributed hydrated zwitterionic chains to rebuild a highly lubricated layer and minimize friction. When shear was removed, the bonds spontaneously reformed, the nanocrown assembled back, and the lubricating components were retained for the next cycle. This mechanically programmed dissociation-reassembly cycle maintained ultralow friction over repeated loading, achieving a >90% lower coefficient of friction than commercial hyaluronic acid. The reactive oxygen species-cleavable linkers enabled targeted drug release in inflammatory joints, effectively reducing IL-6/IL-1β, protecting extracellular matrix integrity, and reversing chondrocyte senescence. In load-driven knee osteoarthritis and frequency-driven temporomandibular joint osteoarthritis model, 6S-NP preserved cartilage, suppressed inflammation, and improved joint morphology. The adaptable design principles of 6S-NP could also be extended to other mechanically and oxidatively stressed degenerative conditions, providing a broadly applicable therapeutic strategy.