Proton‐Driven Deformability Enables Nanozyme‐Integrated Vaccine for Enhanced Tumor Immunotherapy

Abstract Cancer immunotherapy leveraging vaccine‐based approaches has emerged as a promising strategy for long‐term tumor regression and metastasis prevention. However, the design of effective vaccines remains challenging due to the need for efficient lymph node (LN) targeting, dendritic cell (DC) uptake, and robust cellular immunity activation. Here, a proton‐driven, multifunctional nanovaccine (PP@Pt‐OVA) is presented that combines intelligent morphology regulation and nanozyme catalysis to address these challenges. The nanovaccine, comprising PVP@Pt nanozymes and OVA 257–264 peptides encapsulated in PEG‐b‐PAE micelles, undergoes proton‐driven morphology transformation in acidic LN microenvironments, enhancing particle size and reducing PEGylation for optimized LN retention and DC uptake. Once internalized, PVP@Pt nanozyme catalyzes reactive oxygen species (ROS) production, facilitating endosomal escape, antigen cross‐presentation, and DC maturation. PP@Pt‐OVA demonstrated efficient LN targeting, robust CD8 + T cell activation, and significant tumor inhibition in both prophylactic and therapeutic melanoma models, with excellent biocompatibility and minimal systemic toxicity. These findings highlight the potential of PP@Pt‐OVA as a versatile nanovaccine platform, offering a rational design framework for overcoming the limitations of subunit vaccines and advancing cancer immunotherapy.