Jiaxin Cui, Xin Liu, Jingting He, Zhenjie Zhang, Yao Chen
Biomolecules are nature's catalysts and recognition elements, yet their practical use is limited by instability and lack of reusability. Crystalline porous organic frameworks (POFs) have emerged as protective hosts, but the field is now shifting from passive encapsulation toward engineering multi-component synergy. This review introduces a new paradigm: moving beyond single-biomolecule immobilization to construct hierarchical, cooperative systems within POFs. The structural regularity, tunable porosity, and versatile functionality of POFs enable the spatial and functional organization of multiple enzymes, nucleic acids, proteins, small bioactive molecules, and even heterogeneous functional components-forming multi-enzyme cascades, nucleic acid-protein assemblies, protein-protein synergistic systems, and heterogeneous integrations with metal nanoparticles, polymers, inorganic components, biological membranes, and living cells-to create artificial organelles and molecular factories that mimic nature's compartmentalization. These synergistic systems enable efficient cascade catalysis, enhanced stability, and emergent functionalities unattainable by single components. We survey their applications in industrial biocatalysis, environmental remediation, and healthcare, while also critically discussing current challenges and future directions. By establishing multi-component synergy as a new design principle, this review provides a roadmap for the next generation of POF-based biohybrids toward sustainable biotechnologies.