This study investigates the interactions of cationic polyamidoamine (PAMAM) and poly lactic(co-glycolic) acid-polyethylenimine (PLGA-PEI) NPs with catabolically active cartilage ECM. By modeling degradative mechanisms involved in OA using enzymes such as hyaluronidase (HYA), ADAMTS5 (ADA), and collagenase type II (COL) in ex vivo porcine articular cartilage, we aimed to elucidate the impact on NP behavior under pathological conditions. HYA targets small fragments of hyaluronan (HA), considered DAMPs that induces pro-inflammatory responses. ADA mediated depletion of aggrecan (ACAN), a hallmark of OA, contributes to tissue deterioration and joint pain, while COL-induced ECM remodeling weakens the network due to the cleavage of collagen type II (COL2), accelerating degeneration.