Ultrasound-responsive Pickering emulsions enable extracellular matrix disruption for enhanced sonodynamic...

Sonodynamic therapy (SDT) mediated by aggregation-induced emission (AIE) sonosensitizers markedly enhances reactive oxygen species (ROS) generation by overcoming aggregation-caused quenching. However, the dense extracellular matrix (ECM) in solid tumors restricts sonosensitizer penetration and aggregation, aggravates hypoxia, and dampens immune responses, ultimately limiting SDT efficacy. Developing delivery platforms capable of breaching ECM barriers while relieving ECM-induced hypoxia and immunosuppression is therefore essential for improving AIE-SDT and advancing its clinical translation. Inspired by plant seed explosion-mimetic propagation, we develop an ultrasound-responsive Pickering emulation platform (PEO-CST) that drives deep delivery of AIE-sonosensitizer seeds across the ECM via cavitation effect, while concurrently improving the hypoxic and immunosuppressive tumor microenvironment. Unlike conventional microbubbles, PEO-CST encapsulates oxygen-saturated perfluorocarbon as its core, and the chitosan nanogel shell integrates AIE sonosensitizers and inherently activates the cGAS-STING pathway. This architecture increases AIE-sonosensitizer loading capacity and enables ultrasound-responsive ECM breakthrough of AIE-loaded chitosan nanogel like explosion of seeds. Upon ultrasound excitation, the energy core of PEO-CST disrupts ECM barriers, releases oxygen, and activates the cGAS-STING pathway. The resulting deep penetration and aggregation of AIE sonosensitizers, together with reconstruction of the ECM-mediated hypoxic and immunosuppressive milieu, substantially enhances SDT efficacy. This study presents a multidimensional strategy that overcomes ECM barriers, alleviates tumor hypoxia, and activates immune pathways, offering a path toward clinical implementation of SDT.