Synovial Fluid Profile Dictates Nanopracticle Uptake into Cartilage- Implications of the Protein Corona for Novel Arthitis Treatments

A major obstacle for joint drug delivery is to penetrate the dense, negatively charged cartilage matrix. Previous studies have extensively investigated particle approaches to increase uptake efficiency into tissues but have neglected to address potential interactions with the synovial fluid. Here, we developed a nanoparticle (NP) panel with varying PEGylation and incubated them with synovial fluid from either osteoarthritic (OA) or rheumatoid arthritis (RA) patients, or fetal calf serum (FCS). Compared to nonprotein- covered NPs, the formed protein coronas majorly impacted NP uptake into cartilage tissue and dictated their uptake in chondrocytes and monocytes - a measure of targeting efficiency and clearance potential. Utilizing a quantitative proteomics approach, we identified certain families of proteins on all panel members irrespective of the NP modifications. Nonetheless, NP-, and protein-specific differences were also observed between the groups, and candidate proteins were identified that could account for the observed differences. This study is the first to demonstrate how protein coronas from different biological origins impact NP uptake into cartilage, emphasizing the importance of considering the several aspects of the biological microenvironment for successful translation of drug delivery vehicles into clinics.