Starch nanoparticles (SNPs) were synthesized and characterized in vivo for their subacute biotoxicity. Animal experiments revealed that SNPs would not induce changes in inflammatory cytokines and gut microbiota, avoiding damage to mice's organs. Moreover, SNPs were rapidly excreted from the body after 6 h without any accumulation, demonstrating their biosafety. Based on these findings, SNPs were used for beta-lactoglobulin (beta Lg) desensitization by formation of a protein corona. The thermodynamics and time evolution of beta Lg's secondary structure were investigated to address the desensitization mechanism. The results showed-1600 beta Lg molecules onto a single SNP coupled with significant changes in secondary structure formed a stable SNPs-beta Lg corona with binding affinity (Ka) of 8.4 +/- 0.5 x 105 M- 1. Functionally, the decrease of beta-sheet destroyed the conformation of immunoglobulin E (IgE) epitopes and inhibited IgE combining capacity, achieving SNPs' desensitization to beta Lg. Additionally, it takes-2 h to complete changes in beta Lg's surface hydrophobicity and immunoglobulin E (IgE) combining capacity after incubation with SNPs, consistent with the time evolution of structure changes, indi-cating protein corona is response for the desensitization.