Engineering hierarchical macro/mesoporous structures that offer an abundance of accessible binding sites are highly desirable in protein adsorption processes. However, numerous significant challenges remain. Herein, cellulose nanofiber (CNF)-loaded macroporous silica (CNF-MPS) particles were successfully synthesized with a high degree of accessible binding sites by tuning the macropore size of the silica particles and loading a highly carboxylated CNF via smart and rational design. The as-prepared CNF-MPS particles exhibited a high negative charge (similar to-59 mV) and excellent protein adsorption ability (>1000 mg/g) in <5 min. Furthermore, tuning the macropore size influenced the CNF deposition either to the external surface or penetrating within the pores. As a result, the optimum macropore successfully enhances the adsorption capability to >1500 mg/g as a result of improved interconnectivity between the channels. Here exposed macropores of >100 nm allows ingress of protein to the interior structure that houses an abundance of binding sites comprising the dispersed CNF. Additionally, the adsorption kinetics, thermodynamics, and isothermal parameters were studied to analyze the mechanism of lysozyme adsorption. The adsorption process is confirmed to occur spontaneously at any temperature with a pseudo-second-order model describing the kinetic model, and CNF deposition affecting the heterogeneity of the binding sites. (C) 2020 The Society of Powder Technology Japan. Published by Elsevier B.V. and The Society of Powder Technology Japan. All rights reserved.