Osteoarthritis is the most common degenerative joint disease worldwide, yet no intra-articular disease-modifying osteoarthritis drugs (DMOADs) have succeeded in clinical trials due to poor therapeutic outcomes and limited cartilage targeting. Positively charged nanosized carriers have been shown to penetrate the dense, negatively charged cartilage. Here, we synthesized a cationic avidin-biotin-PEG2-kartogenin (Av-bKGN) nanocarrier in a rapid, scalable manner. Over 80 % of Av-bKGN remained stable after 24 h in PBS and simulated synovial fluid, whereas a new kartogenin derivative was predominantly generated in esterase-rich media. Av-bKGN suppressed inflammatory mediators (NO2 - , IL-6) in human chondrocytes and macrophages, and its nanosize (8.7 ± 0.26 nm) and positive charge (+18.3 ± 0.75 mV) enhanced cartilage uptake by 4.3- and 11.4-fold, respectively, and cartilage retention by 2-fold over 10 days in PBS and simulated synovial fluid compared to its neutral coun­ terpart, neutravidin. A custom diffusion chamber showed Av-bKGN diffuses tenfold slower than neutravidin, driven by electrostatic binding to cartilage glycosaminoglycans (GAGs). Combining avidin's delivery platform with bKGN's DMOAD activity reduced GAG loss in in vitro IL-1a-stimulated OA model. A single Av-bKGN dose provided protection equivalent to multiple free-drug doses (25 % reduced GAG loss), with repeated Av-bKGN doses achieved 1.7-fold greater chondroprotection. These findings highlight electrostatic interaction-driven uptake and retention of Av-bKGN as a promising strategy for targeted cartilage therapy.