Engineering Smart Hydrogels Through Dynamic Polymer Networks for Controlled Drug Delivery

Smart hydrogels are increasingly explored as adaptive platforms for controlled drug delivery because their polymer networks can respond dynamically to chemical, biological, and physical cues. Among these systems, dynamic polymer networks formed through reversible covalent and noncovalent interactions provide a unique means of coupling molecular-scale bond exchange with time-dependent changes in hydrogel structure, mechanics, degradation, and therapeutic transport. This review presents an integrated framework linking dynamic crosslink chemistry, exchange kinetics, network properties, and drug-release behavior. Dynamic covalent, supramolecular, metal–ligand, and hybrid network strategies are compared with particular emphasis on how crosslink lifetime, mesh accessibility, swelling, viscoelasticity, stress relaxation, and degradation govern therapeutic cargo loading, retention, diffusion, and release. Representative release mechanisms and kinetic models are discussed together with cargo-specific design considerations for small molecules, proteins and peptides, nucleic acids, and nanoparticle-based therapeutics. Biomedical applications are further considered according to therapeutic requirements and administration routes, including injectable local depots, topical and transdermal delivery, and regenerative systems. Finally, key translational challenges involving physiological complexity, biocompatibility, reproducibility, scale-up, sterilization, and storage stability are critically assessed. By connecting molecular interaction dynamics with network-level behavior and therapeutic performance, this review provides design principles for developing more predictable, programmable, and clinically translatable dynamic hydrogel drug-delivery systems.