Overall, PAMAM-based NPs exhibited higher levels of cytokine expression compared to the larger PLGA counterparts. This is not surprising, as small, charged NPs have been reported to evoke a prominent immunological response due to the biomimicry and large surface area-to-volume ratio. Nonetheless, anti-fouling surface modifications such as PEGylation remain an important factor for small charged particle immunomodulation. Considering that larger particles such as PLGAs are not able to penetrate the dense cartilage tissue, these systems are frequently employed as controlled release depots, consequently necessitating minimal interaction with the immune system. Significantly, the data strongly supports the role of ACAN, a degradation product of ADA, as a considerable DAMP and important biomarker in OA. degeneration and disease progression. Thus, larger particles may serve as better carriers in later stages of OA when the degradation of ECM is advanced, due to their resilience in initiating an immune response. In addition, we observed similar effects between HYA and ADA-induced NP-aggregates in GAG quantification, protein conformation, and cytokine induction, whereas COL conditioning resulted in distinct patterns. Such observations further emphasize the importance of patient-specific drug delivery strategies for complex diseases such as OA.