Ultrasound-responsive composite hydrogels: Design rules for spatiotemporally controlled drug delivery

Ultrasound-responsive composite hydrogels, defined as polymeric networks integrated with acoustically active micro- or nanoparticles, enable spatiotemporally controlled drug delivery through synergistic mechanisms. This review provides a design-oriented analysis of these systems, organized around four fundamental topics that guide rational system development: tuning activation thresholds for safety and specificity, controlling release magnitude and kinetics, achieving repeatable activation for pulsatile dosing, and programming sequential multi-drug delivery. We examine how hydrogel matrix properties (e.g., crosslinking chemistry, mechanical properties, network architecture) and embedded particle characteristics (e.g., gas-filled microbubbles, phase-change droplets, piezoelectric nanoparticles) combine to determine acoustic responsiveness and release behavior. Therapeutic applications across oncology, tissue regeneration, pain management, and metabolic disorder management illustrate how specific design strategies address distinct pathological challenges. We conclude by identifying critical barriers to clinical translation, including precise control in heterogeneous biological environments, long-term stability of dynamic components, and manufacturing scalability, alongside emerging opportunities in adaptive theranostic integration.