Supramolecular Polyzwitterionic Nanoparticles with Engineered pH‐Responsiveness and Cartilage‐Penetration for Osteoarthritis Therapy

Abstract Abnormal friction forces, compact matrix structure, and dynamic acidic microenvironment in osteoarthritis (OA) make it difficult to remodel cartilage regeneration by integrating prominent inflammatory responses and cartilage anabolism. Here, pH‐responsive PSBMA‐ b ‐PColBP@KGN nanoparticles (PSPK NPs) are developed by a simple supramolecular assembly process. PSPK NPs are found to reduce the coefficient of friction (0.028) under high loading pressure (10.41 MPa). The synergistic effect of pH‐responsive KGN release coupling deep penetration promotes cartilage generation in the inflammatory microenvironment. Further, in vivo studies confirm the potential of PSPK NPs in restoring cartilage homeostasis, as evidenced by reduced osteophyte volume, aligned cartilage structures, and abundant cartilage matrix. This study provides novel insights into the synergistic effects of pH‐responsive release, deep penetration, and hydration lubrication on OA treatment, offering a strategy for the design of tissue‐adaptive supramolecular nanoparticles to promote tissue regeneration in inflammation‐related diseases.