Metal coordination at biological interfaces: Mechanisms, therapeutics, and translation

Metal ions are integral to biological systems, serving as catalytic cofactors, structural components, and mediators of key cellular signaling pathways. Understanding their interactions with bioactive molecules at biointerfaces provides valuable insights into the development of metal-based drugs, therapeutic biomaterials, and innovative nanomedicines. This review adopts a bio-interface-centered framework that integrates coordination chemistry, surface chemistry, and biomolecular recognition, underscoring how coordination geometry, ligand kinetics, redox behavior, and hard/soft acid/base preferences affect the interactions of metal complexes with DNA, proteins, lipids, and glycoconjugates. These interactions regulate diverse cellular processes, such as mitochondrial function, signal transduction cascades, and programmed cell death mechanisms, including apoptosis and ferroptosis. This manuscript outlines the major classes of clinically significant metal complexes, along with emerging systems, including metal-organic frameworks, polymeric carriers, and artificial metalloenzymes, designed to provide targeted delivery and catalytic activity at biological interfaces. In particular, this review focuses on the combination of coordination chemistry, nanotechnology, and chemical biology to develop stimuli-responsive frameworks capable of targeted delivery and multifunctional therapeutic effects. This review further examines the role of metal coordination in biomolecular recognition, biointerface regulation, pharmacokinetic behavior, toxicity, and therapeutic performance, thereby linking atomic-level coordination chemistry with cellular and translational outcomes. This bio-interface-centered perspective distinguishes the present review from prior work focused separately on metallodrugs, bioinorganic mechanisms, or coordination chemistry.