Engineering dynamic hydrogels to overcome translational bottlenecks in therapeutic delivery.

Abstract

Hydrogels are promising platforms for the controlled release of drugs, biologics, and living cells, but conventional statically crosslinked networks face important translational limitations, including poor injectability, brittle mechanical behavior, and an inability to recapitulate the time-dependent mechanics of native tissues. Dynamic bonding provides a powerful strategy to overcome these limitations while expanding the design space for controlled release. Non-covalent interactions, including hydrogen bonding, host-guest complexation, metal-ligand coordination, and electrostatics, as well as dynamic covalent chemistries such as imines, hydrazones, oximes, and boronate esters, reversibly break and reform under physiological conditions to generate viscoelastic hydrogels with tunable self-healing, stress relaxation, and energy dissipation. In this review, we describe how the thermodynamics and kinetics of dynamic bonds govern hydrogel injectability, toughness, and viscoelastic behavior, and how these same bond parameters regulate therapeutic cargo transport through affinity-mediated retention of small molecules and dynamic mesh gating of macromolecular cargo. We discuss strategies for programming the release of small-molecule drugs, proteins, nucleic acids, and cells, including stimuli-responsive systems triggered by pH, glucose, enzymes, or competing oligonucleotides. We then examine how dynamic bond exchange shapes the behavior of both delivered therapeutic cells and infiltrating immune cells by controlling matrix viscoelasticity, ligand presentation, and foreign body responses. We highlight applications in adoptive cell therapy, mesenchymal stem cell delivery, and sustained-release vaccine depots, and conclude by outlining the translational challenges, design rules, and key knowledge gaps that must be addressed to advance dynamically crosslinked hydrogels as next-generation controlled-release materials.