Abstract A hierarchical hollownest-structured zeolite (HSZ) microsphere constructed by MWW-nanosheets and its various functionalized derivatives (HSZ-OH, HSZ-NH2 and HSZ-CHO) were firstly applied in the delivery of bovine serum albumin (BSA). Owing to the unique cup-shaped pores on the nanosheets and the abundant prismatic stacking mesopores and macropores in the shell, HSZ materials exhibited higher BSA loading content than other familiar microporous zeolites. More importantly, HSZ-NH2 and HSZ-CHO could release exceeded 50% of the loaded BSA under simulated physiological ion strength condition of pH 7.4 and 5.0, respectively. The adsorption thermodynamic parameters revealed that the loading of BSA on HSZ-OH was an enthalpy-driven process conducted by hydrogen bonds, but an entropy-driven process predominated by electrostatic forces on HSZ-NH2. The pH-sensitive imine bonds between BSA and hydrophobic HSZ-CHO were sensitive to acidic environment, constituting a pH-responsive intelligent protein delivery system. The synchronous fluorescence spectra corroborated that structural alteration of BSA recovered after desorption. The interaction mechanisms were analyzed by determining the physicochemical property of nanosheet surface. The favorable and controllable loading and release performance of HSZs predicted their huge application potential in delivery, slow-release, separation and purification of proteins and protein drugs.