Antigen-Enriched Tumor-Dendritic Cell Fusion Membrane-Coated Metal-Phenolic Nanovaccine Enables Dual T-Cell Activation for Robust Cancer Immunotherapy.

Antigen-enriched tumor vaccines represent a promising strategy for cancer immunotherapy. Nevertheless, their clinical efficacy is often limited by insufficient antigen presentation and low immunogenicity. Here, a novel nanovaccine was developed that synergistically combines mitochondrial fission inhibition, tumor-dendritic cell fusion, and metal-phenolic nanoparticle technology. Tumor cells were pretreated with the mitochondrial fission inhibitor Mdivi‑1, yielding antigen‑enriched cell membranes (CM(M)). Subsequently, these CM(M) were fused with the dendritic cell membranes (DCM) overexpressing B7 biomolecules to create a tumor-dendritic cell fusion membrane (DCCM(M)). R848-loaded metal-phenolic nanoparticles (TF/R848) were further coated with the fusion membrane to create a dual-functional nanovaccine (TF/R848@DCCM(M)). This nanovaccine increases immunogenicity and optimizes antigen presentation. The nanovaccine promotes dual T-cell activation via direct antigen presentation and DC-mediated cross-presentation. TF/R848@DCCM(M) showed remarkable anticancer activity in melanoma-bearing mouse models, greatly reducing tumor development and extending longevity. Moreover, the nanovaccine enhanced the effects of immune checkpoint inhibitors, offering a promising strategy for combination immunotherapy. This study presents a novel, efficient platform for cancer immunotherapy, positioning a versatile and powerful approach for next-generation tumor vaccines.