Surface hydrophobicity and rigidity determines protein corona on orally delivered nanoparticles treating colitis

Disease-specific protein corona adsorbed on nanocarriers determines in vivo delivery efficiency. Macrophages can orchestrate inflammation resolution and mucosa repair, making them a promising therapeutic target in colitis. Here, we show that surface hydrophobicity and rigidity determine colitis-specific intestinal protein corona (C-IPC) on orally delivered nanoparticles for treating colitis, which improves therapeutic efficiency. We show that high surface hydrophobicity boosts overall protein adsorption, leading to improved colon macrophage delivery and therapeutic effect when loaded with budesonide. Moreover, hydrophobicity with high rigidity results in a corona enriched with macrophage-targeting proteins, notably S100A8, generating an optimal C-IPC characterized by both high protein amount and high proportion of targeting proteins. Consequently, high rigidity nanoparticles more effectively attenuates the inflammatory state and restores the immune homeostasis in male rats with colitis. Our work develops a rational strategy of manipulating protein corona formation through physicochemical properties for efficient oral drug delivery, holding broad promise for diverse nanocarriers and pathologies.