Ordered mesoporous metal–organic frameworks (mesoMOFs) were constructed with a uniform pore size up to about 10 nm and thick microporous walls, opening up the possibility for the mass diffusion of large‐size molecules through crystalline MOFs. The synergistic effects based on triblock copolymer templates and the Hofmeister salting‐in anions promote the nucleation of stable MOFs in aqueous phase and the in situ crystallization of MOFs around templates, rendering the generation of a microcrystal with periodically arranged large mesopores. The improved mass transfer benefiting from large‐pore channels, together with robust microporous crystalline structure, endows them as an ideal nanoreactor for the highly efficient digestion of various biogenic proteins. This strategy could set a guideline for the rational design of new ordered large‐pore mesoMOFs with a variety of compositions and functionalities and pave a way for their potential applications with biomacromolecules.

Zr‐based mesoporous metal–organic frameworks (mesoMOFs) with uniform mesochannels and crystallized microporous framework were constructed in a water‐based system using amphoteric surfactants as templates. Aqueous‐phase synthesis guaranteed the formation of rod‐shaped surfactant micelles. Meanwhile, the carboxylate groups of amphoteric surfactants provided the anchoring to bridge Zr‐oxo clusters and surfactant assemblies. As a result, the directed crystallization of MOFs proceeded around cylindrical micelles and the hierarchical micro‐ and mesostructure was produced. The dimensions of mesopores were easily tailored by changing the alkyl chain length of the applied surfactants. The included surfactant was effectively extracted thanks to the exceptional stability of the obtained Zr‐based mesoMOFs. The almost complete occupation of the mesopore by cytochrome c exemplifies the accessibility of the mesochannels, suggesting the potential applications of the obtained mesoMOFs with bulky molecules.