Cytosolic Delivery of Thiolated Mn‐cGAMP Nanovaccine to Enhance the Antitumor Immune Responses

As a stimulator of interferon gene (STING), cyclic dinucleotide activates a broad cellular immune response for anti‐cancer immunotherapy (CIT). However, the inherent of instability of 2′ 3′‐cyclic‐GMP‐AMP (cGAMP) with poor cellular targeting, rapid clearance, and inefficient transport to the cytoplasm seriously hinders cGAMP potency. Here, a thiolated and Mn2+ coordinated cyclic dinucleotide nanovaccine (termed as Mn‐cGAMP NVs) to enable direct cytosolic co‐delivery of cGAMP and Mn2+ to potentiate the antitumor immune response is presented. In the NVs, the fixation cGAMP with Mn2+ ions not only improve its stability, but also potentiate the activation of STING. Meanwhile, the presence of polysulfides on the NVs surface allowed direct cytosolic delivery while avoiding degradation. In this way, the production of cytokines for activating T cells immunity is greatly elevated, which in turn suppressed the primary and distal tumors growth through long‐term immune memory and led to long‐term survival of poorly immunogenic B16F10 melanoma mice. Moreover, by further combining with anti‐PD‐L1 monoclonal antibody, synergistic T cells antitumor immune response is elicited. This work offers a promising strategy to enhance the potency of cGAMP, holding a considerable potential for CIT applications. Herein, a thiolated and Mn2+ coordinated cyclic dinucleotide nanovaccines to direct cytosolic co‐delivery of 2′ 3′‐cyclic‐GMP‐AMP (cGAMP) and Mn2+ is reported. It contemporary improves cGAMP stability and activation of stimulator of interferon gene, which lead to enhance T cells immunity for suppressed the primary tumor growth and distance tumor, holding a considerable potential for cancer immunotherapy applications.