Integrating superlubricative nanomaterials with precision drug delivery for advanced osteoarthritis therapy.

Osteoarthritis (OA) is a degenerative joint disorder characterized by chronic inflammation, impaired lubrication, and progressive cartilage degradation. To address these multifaceted pathologies, we developed a multifunctional nanoparticle, termed HPQ@K, based on hyaluronic acid (HA), for co-delivery of quercetin (QUT) - a compound with anti-inflammatory, antioxidant, and hyaluronidase properties - and kartogenin (KGN), which induces chondroautophagy and cartilage regeneration. QUT was conjugated to HA through reactive oxygen species (ROS)- and pH-sensitive boronate ester linkages, leading to self-assembled micelles that encapsulate KGN and enable stimulus-responsive drug release under inflammatory OA conditions. HPQ@K retains the innate lubricity and biocompatibility of HA, while exhibiting enhanced resistance to enzymatic degradation, thereby prolonging its joint residence time. Its nanospheric structure ensures uniform articular coverage and combines hydration lubrication with a "ball-bearing" effect to achieve superlubricity. In murine chondrocytes, OA models, and human cartilage tissues, HPQ@K enhanced drug bioavailability and enabled spatiotemporally controlled release, mitigating oxidative stress, restoring mitochondrial function, promoting autophagy, and reducing cellular senescence. Furthermore, it significantly lowered friction coefficients and protected cartilage from mechanical damage. Collectively, HPQ@K constitutes an all-in-one nanotherapeutic platform that concurrently targets inflammation, restores joint lubrication, and facilitates cartilage repair, offering a comprehensive triple-therapy strategy for advanced OA.