Dynamic Covalent Biomacromaterials from Molecular Design to Biomedical Function

Dynamic covalent biomacromaterials are redefining the design of adaptive soft materials by integrating the structural diversity and biological functionality of biomacromolecules with reversible covalent bond exchange. In contrast to permanently cross-linked networks, these materials can continuously reorganize their internal architecture in response to mechanical, chemical, and biological stimuli, enabling self-healing, stress relaxation, injectability, shape adaptation, programmable degradation, and spatiotemporally controlled molecular transport. This review critically examines the molecular and network-level principles that govern such adaptive behavior, emphasizing how bond-exchange chemistry, reaction kinetics, cross-link density, network topology, and biomacromolecular architecture collectively dictate macroscopic performance. Major dynamic covalent motifs, including imine and hydrazone bonds, boronic esters, disulfides, reversible Diels–Alder adducts, and related exchangeable linkages, are analyzed in the context of polysaccharides, proteins, peptides, nucleic acids, and other biologically derived macromolecules. Rather than treating dynamic chemistry solely as a cross-linking strategy, we highlight how molecular exchange propagates across hierarchical length scales to regulate mechanics, molecular diffusion, cell–material interactions, tissue integration, degradation, and therapeutic release. Recent developments in injectable hydrogels, regenerative matrices, wound-healing platforms, drug and gene delivery systems, bioadhesives, and responsive biomedical interfaces are critically assessed to identify both emerging opportunities and persistent limitations. The remaining challenges lie in reconciling exchange kinetics with mechanical robustness, physiological stability, cytocompatibility, reproducibility, and manufacturability, all of which remain central to successful biomedical translation. By establishing explicit relationships between molecular bond dynamics, network adaptation, and biological function, this review provides a unifying framework for engineering next-generation biomacromaterials capable of dynamically interacting with, responding to, and integrating within complex biological environments.