The chapter discusses the advancements in metal–drug coordination nanomaterials and hydrogels for enhanced drug delivery. Traditional drug delivery methods often rely on adsorption or encapsulation of drugs into nanomaterials, but these methods can pose long-term toxicity concerns. Recent developments have focused on using drug molecules as ligands to form coordination bonds with metal ions, creating various nanomaterials and soft materials. These materials, including nanoparticles and hydrogels, can be tailored to improve drug efficacy and reduce toxicity through the grafting of targeting ligands. The chapter highlights the advantages of metal–drug coordination, such as lower metal content, enhanced lipophilicity of drugs, and the ability to respond to disease microenvironments. Metal ions, such as iron, copper, and zinc, exhibit unique physicochemical properties that can be leveraged for efficient drug delivery and synergistic therapy. The formation of coordination complexes can enhance drug stability in the bloodstream, reduce toxicity, and facilitate controlled release. The text also reviews specific examples of metal–drug coordination nanomaterials, including nanoparticles and hydrogels, for the delivery of small molecule drugs, nucleic acids, and proteins. For small molecule drugs, examples include pteridines, bisphosphonates, anthracyclines, steroids, and nucleoside analogs. For nucleic acids, the focus is on CpG oligonucleotides, antisense DNA, DNAzymes, and therapeutic RNA. For protein drugs, the examples include RNase A and serum albumin. Finally, the chapter discusses the potential future directions in fundamental research, materials science, and medicine, emphasizing the need for further studies to optimize the design and application of metal–drug coordination nanomaterials and hydrogels for enhanced drug delivery.The chapter discusses the advancements in metal–drug coordination nanomaterials and hydrogels for enhanced drug delivery. Traditional drug delivery methods often rely on adsorption or encapsulation of drugs into nanomaterials, but these methods can pose long-term toxicity concerns. Recent developments have focused on using drug molecules as ligands to form coordination bonds with metal ions, creating various nanomaterials and soft materials. These materials, including nanoparticles and hydrogels, can be tailored to improve drug efficacy and reduce toxicity through the grafting of targeting ligands. The chapter highlights the advantages of metal–drug coordination, such as lower metal content, enhanced lipophilicity of drugs, and the ability to respond to disease microenvironments. Metal ions, such as iron, copper, and zinc, exhibit unique physicochemical properties that can be leveraged for efficient drug delivery and synergistic therapy. The formation of coordination complexes can enhance drug stability in the bloodstream, reduce toxicity, and facilitate controlled release. The text also reviews specific examples of metal–drug coordination nanomaterials, including nanoparticles and hydrogels, for the delivery of small molecule drugs, nucleic acids, and proteins. For small molecule drugs, examples include pteridines, bisphosphonates, anthracyclines, steroids, and nucleoside analogs. For nucleic acids, the focus is on CpG oligonucleotides, antisense DNA, DNAzymes, and therapeutic RNA. For protein drugs, the examples include RNase A and serum albumin. Finally, the chapter discusses the potential future directions in fundamental research, materials science, and medicine, emphasizing the need for further studies to optimize the design and application of metal–drug coordination nanomaterials and hydrogels for enhanced drug delivery.