Advances in metal ion-mediated macromolecular drug delivery

Metal ions, by virtue of their coordination versatility and intrinsic biological roles, have emerged as powerful mediators for the delivery and functional modulation of biomacromolecular drugs (proteins, peptides, and nucleic acids). This narrative review comprehensively outlines the mechanisms, applications, and challenges of metal-ion-driven biomacromolecular drug delivery systems. Specifically, we provide a focused and systematic overview of the molecular mechanisms by which metal ions interact with macromolecules, and how these interactions are harnessed to construct four major classes of delivery platforms: (1) metal-mediated self-polymerization; (2) biomimetic mineralization; (3) biomolecule-templated metal-organic frameworks MOFs; and (4) metal-controlled in situ mineralizing hydrogels. We discuss how these platforms improve transport across critical biological barriers (oral, cutaneous, blood-brain, and cellular membranes) and elicit synergistic therapeutic functions. Potential limitations-including ion-associated toxicity, premature cargo release, and metal-induced drug inactivation-are analyzed and paired with practical mitigation strategies. We conclude by outlining design principles and future directions to balance functional performance and biosafety, aiming to guide the rational development and clinical translation of programmable, metal-coordinated macromolecular therapeutics.