Liquid Metal Nanoparticles-Mediated Mitochondrial Damage Enhances Immunogenic Cell Death for Cancer Vaccine Therapy.

Abstract

Cancer vaccines face limitations due to the immunosuppressive tumor microenvironment (TME) and the low immunogenicity of tumor antigens. Immunogenic cell death (ICD), triggered by mitochondrial dysfunction, provides a promising strategy to enhance tumor antigen release and immune activation. However, actively amplifying mitochondrial damage-induced ICD remains challenging. In this study, we developed a vaccine in which liquid metal nanoparticles (LMPs) target tumor cells, undergo self-assembly and aggregation on the cell surface to achieve efficient uptake, fuse intracellularly to prolong retention, and release Ga³⁺ ions through an iron-substitution pathway to induce mitochondrial damage, thereby triggering ICD. In combination with irreversible electroporation (IRE), this approach mediates durable tumor-specific immunotherapy. Specifically, LMPs target tumor cell integrin αvβ6 to initiate self-assembly and aggregation, leading to efficient cellular internalization. Within the acidic lysosomal environment, LMPs undergo fusion and partially escape into the cytosol, enabling prolonged intracellular retention and sustained release of Ga³⁺ ions. The released Ga³⁺ disrupts mitochondrial structure and inhibits electron transport via iron substitution, resulting in pronounced mitochondrial damage. Synergistic IRE and LMPs increase the liberation of mitochondrial damage-associated DAMPs and tumor antigens, driving robust ICD and long-term systemic antitumor immunity. This dual-modality strategy provides a blueprint for nanomaterial-enabled amplification of ICD in cancer immunotherapy.