Lymphocyte-Mimicking Sonosensitizers Boost Cancer Immunotherapy via Sequential Ultrasound Activation

Effective initiation of the cancer-immunity cycle is the core challenge of tumor immunotherapy, which relies on the coordinated antigen release and immunostimulation. To address this issue, this work introduced a novel lymphocyte-mimicking sonosensitizer using Mn-doped hollow Prussian blue nanoparticle (Mn-HP) for cancer sonodynamic therapy (SDT) to efficiently evoke anticancer immunity. The prepared Mn-HP have unique architecture to amplify ultrasonic cavitation effects, boosting spatially controlled reactive oxygen species (ROS) production. Through the effective combination of the Mn-HP and lymphocytes, the Lymphocyte-mimicking sonosensitizer (Lymphocytes-Mn-HP, LM) with the “Homing effect” is constructed. The sequenced dual-ultrasound strategy employs high-power ultrasound (2.0 W cm⁻²) stimulation (excessive ROS) for tumor antigen release and low-power ultrasound (0.5 W cm⁻²) stimulation (moderate ROS) for lymph node to active immune cells, enabling precise spatial-temporal controlled ROS generation while preserving immune function. Both in vitro and in vivo studies demonstrated significant tumor suppression through initiating the cancer-immunity cycle, offering a transformative paradigm for SDT-immunotherapy integration.