Abstract:Breakthrough advances in nanotechnology have substantially enhanced lymph node (LN) targeting efficiency and immune cell uptake of nanovaccines, establishing novel avenues for tumor immunotherapy. Nevertheless, current nanovaccines predominantly accumulate in subcapsular sinuses (SCS) or superficial cortical regions post‐lymphatic transport, failing to traverse anatomical barriers to reach the T cell‐enriched paracortex—a critical delivery bottleneck that severely limits full activation of cellular immunity. Furthermore, the absence of tumor‐specific endogenous stimuli in LN microenvironments invalidates conventional environment‐responsive delivery strategies. Herein, “dynamically size‐change nanovaccine” (DashVax), a time‐controlled self‐disassembling nanovaccine is presented that achieves dynamic size transition from 102 to 5 nm via physiologically regulated imine bond hydrolysis. This design capitalizes on the lymphatic drainage superiority of large particles and tissue‐penetrating capacity of small units, achieving a breakthrough 7.3‐fold enhancement in paracortical antigen delivery compared to non‐size‐change nanovaccines (NoncVax). DashVax demonstrates robust antigen‐specific immune responses and tumor growth suppression in both B16‐OVA and MC38 tumor models. This exogenous stimulus‐free temporal delivery strategy not only redefines nanovaccine design principles but also elucidates fundamental correlations between intranodal delivery kinetics and immune activation efficacy.
