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Codelivery nanovaccines of antigens and adjuvants have achieved positive therapy for cancer immunotherapy. The insufficient immunogenicity of these vaccines leads to the difficulty of eliciting robust immune effects for immune clearance due to the inadequate loading efficiency, complex preparation processes, low safety concerns, and weak immune responses. Herein, a visible codelivery nanovaccine of an antigen and adjuvant based on self-cross-linked antigen nanoparticles (ovalbumin nanoparticles (ONPs)) combined with the adjuvant (CpG) for cancer immunotherapy was prepared using antigens themselves as carriers. ONPs not only provide sufficient antigens for continuous simulation of the immune response with high antigen loading efficiency but also serve as natural carriers of CpG. In vitro and in vivo experiments proved that ONPs-CpG can elicit a robust immune response including DC maturity, T cell activation, and IFN-γ production. ONPs-CpG induced strong tumor-specific immunity and exhibited remarkable antitumor immunotherapy effects in vivo using mouse models of lymphoma. Furthermore, to perform the precise vaccine delivery, the dual fluorescent codelivery nanovaccine was monitored in real time in vivo by the visible imaging method. With regard to migration tracking, fluorescence imaging allowed for both high resolution and sensitivity of visible detection based on the fluorescence of ONPs and CpG. The multifunctional nanovaccine could function as a robust platform for cancer immunotherapy and a visible system for antigen–adjuvant tracking.

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Combined nanovaccine can generate robust and persistent antigen-specific immune responses. A combined nanovaccine was developed based on antigen-loaded genipin-cross-linked-polyethyleneimine-antigen nanoparticles and in vivo multispectral fluorescence imaging tracked the antigen delivery of combined nanovaccine. The inner layer antigen nanoparticles carried abundant antigens by self-cross-linking for persistent immune response, whereas the outer antigen on the surface of antigen nanoparticles provided the initial antigen exposure. The delivery of combined nanovaccine was tracked dynamically and objectively by the separation of inner genipin cross-linked antigen nanoparticle and the outer fluorescent antigen. The immune responses of the combined nanovaccine were evaluated including antigen-specific CD4 and CD8 T-cell responses, IgG antibody level, immunological memory, and CD8 cytotoxic T lymphocyte responses. The results indicated that the inner and outer antigens of combined vaccine can be tracked in real time with a programmed delivery by the dual fluorescence imaging. The programmed delivery of the inner and outer antigens induced strong immune responses with a combination of a quick delivery and a persistent delivery. With adequate antigen exposure, the dendritic cells were effectively activated and matured, and following T cells were further activated for immune response. Compared with a single nanoparticle formulation, the combined nanovaccine exactly elicited a stronger antigen-specific immune response.