Dynamic coordination engineering of gallium biomaterials: A biological accessibility framework for therapeutic...

Gallium (Ga)-based biomaterials have emerged as versatile therapeutic platforms owing to the iron-mimicking properties and broad biological activities of gallium. Coordination engineering regulates Ga speciation, stability, transport, and therapeutic activation; however, optimizing individual physicochemical properties does not necessarily improve biological performance. Excessive coordination stability may restrict ligand exchange and therapeutic activation, whereas insufficient stability may cause premature dissociation, nonspecific exposure, and reduced target delivery. In this Review, we propose Biological Accessibility as a multidimensional, time-dependent property describing the spatiotemporal availability of biologically active gallium species to relevant biological environments, cells, and molecular or tissue targets throughout the therapeutic lifecycle. We first examine ligand chemistry, coordination thermodynamics, ligand-exchange kinetics, gallium speciation under physiological conditions, and disease-responsive coordination evolution. We then review representative coordination-engineered gallium platforms and their applications in antibacterial therapy, immunomodulation, cancer treatment, bone regeneration, bioimaging, and theranostics, highlighting coordination-regulated transport, localization, cellular accessibility, activation, retention, and clearance. Building on these advances, we develop a dynamic framework linking continuous coordination evolution with Biological Accessibility across systemic, pathological, and intracellular environments. We further discuss Therapeutic and Off-target Accessibility, disease-specific accessibility windows, mechanistic attribution of biological functions, quantitative evaluation, in vivo coordination evolution, predictive modeling, artificial intelligence-assisted design, biosafety, and clinical translation. This framework provides a conceptual basis for accessibility-guided design of next-generation gallium biomaterials and broader coordination-engineered therapeutic systems.