Nanoparticle Porosity Modulates Protein Corona Formation and Macrophage Uptake in Synovial Fluid

Intra-articular delivery of nanoparticles offers promising therapeutic potential for joint diseases. Upon exposure, nanoparticles acquire a protein corona that modulates their biological identity and cellular uptake. While porous nanoparticles are commonly employed for enhanced loading capacity, the influence of porosity on protein corona formation and immune recognition remains poorly defined. In this study, we systematically investigated the role of nanoparticle porosity in shaping the synovial protein corona and its downstream effects on macrophage uptake. Solid and mesoporous silica nanoparticles with similar sizes and negative surface charges were synthesized and incubated in ovine synovial fluid. Proteomic profiling revealed that porous nanoparticles absorbed significantly more proteins, including higher levels of opsonins such as immunoglobulins and complement C3, whereas solid nanoparticles were enriched in dysopsonins like apolipoprotein A-I and albumin. Functional assays demonstrated that protein coronas significantly reduced macrophage uptake of solid nanoparticles, whereas porous nanoparticles showed no notable change in phagocytosis. Collectively, these findings indicate that while nanoparticle porosity critically influences the composition of the synovial protein corona, smooth-surfaced solid nanoparticles exert a more substantial inhibitory effect on macrophage uptake. This work offers valuable insights for the rational design of nanocarriers for intra-articular drug delivery and enhances the translational potential of nanomedicines in the treatment of joint diseases.