A Morphology‐Driven Cascade Delivery of Antigens for Potent T Cell Immunity

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.