Hierarchical Nanorocket for spatially coordinated regulation of glycosaminoglycan deposition and metabolism in cartilage.

Osteoarthritis (OA) is characterized by progressive glycosaminoglycan (GAG) depletion caused by insufficient matrix replenishment and excessive proteoglycan catabolism. Here, we developed a spatially coordinated strategy that integrates GAG deposition in the cartilage extracellular matrix (ECM) with intracellular regulation of GAG enrichment and degradation in chondrocytes. To achieve this strategy, we engineered a hierarchical "Nanorocket" comprising a chondroitin sulfate (CS)-cationic peptide Booster and an HDMBr/siADAMTS5 Satellite. The Nanorocket facilitated cartilage penetration and prolonged the intra-articular retention of both components. The Booster supported CS deposition within the cartilage extracellular matrix, whereas the internalized Satellite increased CHPF/CHSY2 expression and silenced ADAMTS5, thereby promoting GAG enrichment while limiting proteoglycan degradation. This coordinated regulation preserved GAG content, reduced matrix porosity, and maintained the mechanical properties of human cartilage explants. In a surgical OA mouse model, periodic treatment preserved cartilage thickness and matrix integrity, mitigated subchondral bone alterations, and improved gait performance. These findings establish the proof-of-concept feasibility of spatially coordinating GAG deposition and metabolism to preserve cartilage homeostasis during early OA progression.