Transformable Gel‐to‐Nanovaccine Enhances Cancer Immunotherapy via Metronomic‐Like Immunomodulation and Collagen‐Mediated Paracortex Delivery

Abstract The generation of non‐exhausted effector T‐cells depends on vaccine's spatiotemporal profile, and untimely delivery and low targeting to lymph node (LN) paracortex by standard bolus immunization show limited efficacy. By recapitulating the dynamic processes of acute infection, a bioadhesive immune niche domain (BIND) is developed that facilitates the delivery of timely‐activating conjugated nanovaccine (t‐CNV) in a metronomic‐like manner and increased the accumulation and retention of TANNylated t‐CNV (tannic acid coated t‐CNV) in LN by specifically binding to collagen in subcapsular sinus where they gradually transformed into TANNylated antigen–adjuvant conjugate by proteolysis, inducing their penetration into paracortex through the collagen‐binding in LN conduit and evoking durable antigen‐specific CD8 + T‐cell responses. The BIND combined with t‐CNV, mRNA vaccine, IL‐2, and anti‐PD‐1 antibody also significantly enhanced cancer immunotherapy by the dynamic modulation of immunological landscape of tumor microenvironment. The results provide material design strategy for dynamic immunomodulation that can potentiate non‐exhausted T‐cell‐based immunotherapy.