Spatiotemporal Controllable Sono‐Nanovaccines Driven by Free‐Field Based Whole‐Body Ultrasound for Personalized Cancer Therapy

Abstract Therapeutic cancer vaccines fail to produce satisfactory outcomes against solid tumors since vaccine‐induced anti‐tumor immunity is significantly hampered by immunosuppression. Generating an in situ cancer vaccine targeting immunological cold tumor microenvironment (TME) appears attractive. Here, a type of free‐field based whole‐body ultrasound (US)‐driven nanovaccines are constructed, named G5‐CHC‐R, by conjugating the sonosensitizer, Chenghai chlorin (CHC) and the immunomodulator, resiquimod (R848) on top of a super small‐sized dendrimeric nanoscaffold. Once entering tumors, R848 can be cleaved from a hypoxia‐sensitive linker, thus modifying the TME via converting macrophage phenotypes. The animals bearing orthotopic pancreatic cancer with intestinal metastasis and breast cancer with lung metastasis are treated with G5‐CHC‐R under a free‐field based whole‐body US system. Benefit from the deep penetration capacity and highly spatiotemporal selectiveness, G5‐CHC‐R triggered by US represented a superior alternative for noninvasive irradiation of deep‐seated tumors and magnification of local immune responses via driving mass release of tumor antigens and “cold‐warm‐hot” three‐state transformation of TME. In addition to irradiating primary tumors, a robust adaptive anti‐tumor immunity is potentiated, leading to successful induction of systemic tumor suppression. The sono‐nanovaccines with good biocompatibility posed wide applicability to a broad spectrum of tumors, revealing immeasurable potential for translational research in oncology.