Porous nanoparticles, such as mesoporous silica nanoparticles (MSNs), have garnered significant interest for biomedical applications. Recently, MSNs with large radial pores have attracted increased attention because their unique pore structure and large pore size are suitable for delivering large molecules such as proteins and genes. Upon entry into biological systems like the bloodstream, nanoparticles quickly form a 'protein corona,' leading to alterations in their interactions with immune cells. In this study, we investigated the formation of protein corona on MSNs with large radial pores and various surface modifications using mass spectrometry. We also examined the effects of protein corona on the interaction between MSNs and macrophages. We prepared MSNs with large, cone-shaped radial pores (>30 nm) and six different functional groups, resulting in nanoparticles with neutral, negative, and positive surface charges. Our findings indicate that surface functional groups significantly alter the composition of the protein corona, affecting the bio-nano interaction of these surface-modified MSNs with macrophages. Notably, nanoparticles with similar surface charges exhibited distinct corona characteristics and were internalized differently by macrophages. This underscores the crucial role of the protein corona in determining the fate, behavior, and biological responses of nanoparticles. Our research sheds light on the significance of understanding and controlling protein corona formation to optimize the design and functionality of nanoparticle-based biomedical applications.