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

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.