Acoustic‐Responsive Hydrogel‐Bubble Microspheres (HBMS) for On‐Demand Programmable Drug Delivery

ABSTRACT Biocompatible hydrogel materials loaded with therapeutic cargo have attracted significant attention in biomedical and clinical drug delivery. Various chemical and physical stimuli strategies have been developed for the on‐demand drug release; however, challenges remain in effectively triggering drug release from hydrogels in deep tissues and controlling release kinetics. To overcome these challenges, we developed acoustically responsive hydrogel‑bubble microspheres (HBMS), which feature a built‑in compressible bubble core. This core functions as an intrinsic acoustic amplifier, transducing ultrasound energy into localized high‐frequency oscillations within the hydrogel shell. This enables on‑demand payload release with low activation energy input. Experimentally, a microfluidic system was employed for the high‐throughput production of HBMS, allowing precise control over droplet size and gas‑core ratio. The HBMS exhibited significantly enhanced ultrasound‐triggered payload release compared with conventional hydrogel microspheres (HMP), achieving significantly greater payload release even at low acoustic energy. Moreover, this strategy proved therapeutic efficiency in a mouse model of oxygen‐induced retinopathy (OIR). This HBMS exhibits excellent acoustically responsive performance, mitigates the risk of thermal damage, and avoids the introduction of chemical or heterogeneous triggering components. With its efficient energy conversion, programmability, injectability, and low‑cost fabrication, HBMS represents a promising platform for ultrasound‐programmable drug delivery in biomedical applications.