Abstract

Subunit vaccines are hampered by their inability to elicit robust cellular immunity and cross-protection. The spatiotemporal fate of vaccine components within the body is key to overcoming this hurdle. Here, we report a cascade “Lymph nodes–Antigen presenting cells–Endoplasmic reticulum (LAE)” delivery strategy enabled by engineering the surface topography of nanoparticles. We designed mesoporous silica nanoparticles with smooth, short-spiked, and long-spiked (SNL) morphologies. Among them, SNL showed superior antigen peptide delivery and APC activation. Mechanistically, SNL enhanced Piezo1-mediated calcium influx through mechanical stimulation, promoting dendritic cell activation and increasing antigen trafficking to the endoplasmic reticulum (ER), a key site for cross-presentation. Capitalizing on this ER-targeting capability, we co-loaded the STING agonist 2′3′-cGAMP with antigen peptides into SNL, yielding synergistic immune activation. This combination induced potent CD8 + T cell responses, delayed tumor progression in lymphoma and cervical cancer models, and conferred cross-protective immunity in a SARS-CoV-2 vaccination model. Our study establishes nanoparticle morphology as an important design parameter for orchestrating the precise intracellular delivery of vaccine components, offering a generalizable platform for next-generation vaccines.