Quantitative design principles for biofunctional metal–organic frameworks: Stability thresholds, biointerface energetics, and therapeutic applications

Metal-organic frameworks (MOFs) combine crystalline order with exceptional coordination-chemical tunability, enabling systematic control over metal-ligand bonding, lattice dynamics, and interfacial energetics. Although MOFs have been widely explored for biomedical applications-including drug delivery, imaging, and sensing-their behaviour under physiological conditions remains difficult to predict due to the lack of quantitatively defined, coordination-driven design principles. Consequently, most reported systems continue to be developed through empirical synthesis-evaluation cycles that incompletely sample the accessible chemical space. Across established MOF families, hydrolytic stability and biological performance vary by more than an order of magnitude and are governed primarily by coordination chemistry rather than framework topology alone. Zinc-based frameworks such as MOF-5 and ZIF-8 undergo rapid proton-assisted ligand displacement and framework collapse on the order of hours in phosphate-buffered saline, whereas zirconium-based UiO-66 and UiO-67 preserve their crystallographic integrity for several days under identical conditions. These contrasting behaviours correlate systematically with coordination-derived activation barriers, adsorption energetics governing biointerface formation, cargo-framework binding strengths, and surface-charge-dependent uptake pathways. This review introduces a semi-quantitative Interaction-Energy Landscape (IEL) framework that links molecular-level coordination energetics to experimentally reported trends in hydrolytic and structural stability, biointerface evolution, and functional performance. By consolidating recurring coordination-derived energetic constraints across biofunctional MOFs, the IEL framework defines a transferable design envelope connecting coordination chemistry with emergent biological function, showing how adaptive biofunctionality arises from deliberately constrained interaction-energy landscapes rather than intrinsic material "intelligence".