Cloaking Silica Nanoparticles with Functional Protein Coatings for Reduced Complement Activation and Cellular Uptake

Silica-coated nanoparticles are widely used in biomedical applications such as theranostics, imaging, and drug delivery. While silica-coated nanoparticles are biocompatible, experimental evidence shows that they can trigger innate immune reactions, and a broader understanding of what types of reactions are caused and how to mitigate them is needed. Herein, we investigated how the noncovalent surface functionalization of silica nanoparticles with purified proteins can inhibit nanoparticle-induced complement activation and macrophage uptake, two of the most clinically relevant innate immune reactions related to nanomedicines. Silica nanoparticles were tested alone and after coating with bovine serum albumin, human serum albumin, fibrinogen, complement factor H (FH), or immunoglobulin G (IgG) proteins. Enzyme-linked immunosorbent assays measuring the generation of various complement activation products indicated that silica nanoparticles induce complement activation via the alternative pathway. All protein coatings other than IgG protected against complement activation to varying extents. Most proteins acted as steric blockers to inhibit complement protein deposition on the nanoparticle surface, while FH coatings were biologically active and inhibited a key step in the amplification loop of complement activation, as confirmed by Western blot analysis. Flow cytometry and fluorescence microscopy experiments further revealed that complement activation-inhibiting protein coatings blunted macrophage uptake as well. Taken together, our findings demonstrate a simple and effective way to coat silica nanoparticles with purified protein coatings in order to mitigate innate immune reactions. Such methods are readily scalable and might constitute a useful strategy for improving the immunological safety profile of silica and silica-coated nanoparticles as well as other types of inorganic nanoparticles.