Therapies targeting joint pathologies by local, intra-articular injections, first encounter the synovial fluid, a protein-rich ultra-filtrate of plasma. Protein adhesion can profoundly influence the fate of NPs, from increased internalization to immune-mediated clearance. If NPs manage to evade lymphatic or macrophage-mediated clearance, they can penetrate the dense extracellular matrix (ECM) of cartilage, where chondrocytes reside. The formation of a protein corona (PC), comprising of proteins and other biomolecules, depends on a range of individual-specific physiological factors. Our previous study revealed how the different compositions of arthritic patient synovial fluids influenced and hampered the uptake of positively charged NPs into cartilage explants and joint-related cells. Additionally, other studies have shown that the protein adsorption profile varies with health status, and that PC composition correlates with tissue pathology. The importance of tissue disintegration is particularly evident for degenerative diseases such as osteoarthritis (OA). OA progression involves the degradation of cartilage ECM components mediated by proteolytic enzymes, namely metalloproteases and glycoside hydrolases. Under healthy conditions, cartilage ECM components form a structural network with optimal mechanical properties crucial for load resistance. However, in OA, biomolecules such as glycosaminoglycans (GAGs), proteoglycans, and collagens are cleaved and released into the synovial fluid, compromising tissue integrity. Some released components act as damage-associated molecular patterns (DAMPs) to influence immunomodulation, inflammation and disease perpetuation. We hypothesized that damaged tissue structures and DAMP formation complement PC formation around the charged nanocarriers, impacting their immunological response. OA progression is highly dependent on immune system activation, thus, investigating drug carrier interactions with cells, surrounding tissues, and their structures is crucial for developing effective nanotherapeutics for arthritis treatment.