Nanobubble‐Based Acoustical Bursting of Nuclear Membrane for Interleukin‐33 Release Induces Eosinophil‐Mediated Cancer Immunotherapy

Abstract Despite noteworthy advances in cancer immunotherapy, the understanding of effective strategies to harness eosinophils in anti‐cancer immunity, which is critical for cytotoxic T ‐cell recruitment, remains limited. In particular, interleukin‐33, which is essential for eosinophil activation, is chromatin‐bound and lacks efficient extracellular release mechanisms for its intact form. Here, a nanobubble‐based acoustical cancer cell‐bursting strategy (NanoBurst) is reported to elicit eosinophil‐mediated cancer immunity by releasing damage‐associated molecular patterns (DAMPs). NanoBurst consists of polymeric nanoparticles encapsulating a gas precursor, designed to effectively disrupt cancer cell membranes upon exposure to ultrasound. This process triggers the efficient release of both nucleus‐derived (e.g., high‐mobility group nucleosome‐binding domain‐1, gasdermin E, interleukin‐33) and cytoplasm‐derived DAMPs, initiating the eosinophil‐mediated immune cascade. Consequently, NanoBurst induces direct tumoricidal effects by activating eosinophils and enhances anti‐cancer immunity by recruiting NK cells and cytotoxic T ‐cells in vivo. When combined with a dipeptidyl peptidase‐4 (DPP4) inhibitor, an inducer of eosinophil‐mediated chemotaxis, NanoBurst effectively inhibits the growth of primary tumors and the metastasis to the lung in a CT26 tumor‐bearing mouse model. Notably, boosting eosinophil‐mediated anti‐cancer immunity with NanoBurst‐DPP4 inhibitor shows superior efficacy for tumor suppression compared to immune checkpoint inhibitors.