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While vaccination remains the most cost\u2010effective control strategy, emerging virulent variants with enhanced immune evasion capabilities have compromised conventional vaccines, manifesting as short\u2010lived protection, suboptimal efficacy, and risks of latency reactivation. To overcome rapid antigen clearance and undefined immunomodulatory mechanisms in traditional emulsion vaccines, we engineered three nanoemulsions with distinct architectures and sizes: an oil\u2010in\u2010water nanovaccine (O\/W nanovaccine, 163.1 \u00b1 3.84\u00a0nm), a water\u2010in\u2010oil\u2010in\u2010water nanovaccine (W\/O\/W nanovaccine, 32 \u00b1 4.04\u00a0nm), and a Pickering emulsion nanovaccine (326.07 \u00b1 9.19\u00a0nm). The immunogenicity and biocompatibility of nanoemulsion formulations are systematically evaluated through in vitro cellular models, followed by comprehensive in vivo investigations in murine\/porcine models to elucidate immune mechanisms, protective efficacy, and challenge resistance. All formulations demonstrated immunostimulatory potential with distinct functional advantages. O\/W nanovaccine exhibited superior antigen\u2010presenting cell uptake efficiency and sustained cytokine induction. W\/O\/W nanovaccine showed maximal dendritic cell activation and high\u2010titer neutralizing antibodies. Pickering emulsion nanovaccine enhanced specific antibody titers. In addition, mechanistic studies revealed that nanoscale lymphatic targeting of O\/W nanovaccine and W\/O\/W nanovaccine leveraged immune cell size preferences for polyfunctional cytokine release. Multi\u2010layered design of W\/O\/W nanovaccine enabled compartmentalized antigen delivery, induced CD8+ T cell response, and synergistically enhanced cross\u2010presentation to elicit coordinated humoral and cellular immunity. Particulate\u2010stabilized interface of Pickering emulsion nanovaccine enhanced humoral immunity via DC\u2010mediated IFN\u2010\u03b3 hyper\u2010secretion and CD4+ T cell differentiation. Furthermore, all nanovaccines demonstrated higher protective efficacy compared to commercial vaccines in animal challenge models infected with PRV, O\/W nanovaccine achieved 100% survival in mice while exhibiting the lowest viral shedding in pigs. This study establishes a transformative prevention paradigm against PRV through nanovaccine engineering, providing critical insights for developing next\u2010generation veterinary vaccine platforms.<\/jats:p>","DOI":"10.1002\/adhm.202503382","type":"journal-article","created":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T11:41:39Z","timestamp":1764762099000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi\u2010Architecture Nanovaccines Against Pseudorabies Virus and Particle Size\u2010Governed Immune Activation Mechanisms"],"prefix":"10.1002","volume":"15","author":[{"given":"Meng","family":"Zhang","sequence":"first","affiliation":[{"name":"Institute of Environment and Sustainable Development in Agriculture Chinese Academy of Agricultural Sciences  Beijing P. R. 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