A Rationally Designed Cyclic Dinucleotide Amplifier Potentiating STING Activation for Cancer Immunotherapy

Abstract Cyclic dinucleotides (CDNs) are natural immunotherapeutic agents that activate the cyclic guanosine monophosphate‐adenosine monophosphate synthase and the stimulator of interferon genes (cGAS‐STING) pathway for tumor immunotherapy. However, the rapid clearance, poor serum stability, low specificity and membrane permeation restrained their effectiveness and induced side effects. Here, a tumor microenvironment‐responsive biomimetic nanoparticle (LZPG) is designed with cobalt‐containing metal‐organic frameworks core (ZIF‐67) and surface lipid bilayer for efficient CDNs delivery and synergistic STING activation. The lipid membrane‐coated ZIF‐67 is fabricated by the filming‐rehydration method and cyclic dinucleotides are incorporated via a simple remote loading approach with the efficiency of cGAMP ≈99%. LZPG swiftly releases cGAMP and Co 2+ upon accumulating in the acidic environment, synergistically activating the cGAS‐STING pathway and inducing the secretion of type I interferon and pro‐inflammatory cytokines for specific T cell response. Moreover, LZPG alleviated the immunosuppressive TME through decreasing regulatory T cells and polarizing M2 macrophages to the M1 phenotype, thus unleashing a cascade adaptive immune response. Remarkably, LZPG showed potent STING activation in human‐derived tumor samples, implying its potential for clinical translation. This study demonstrated an effective and novel strategy to amplify STING activation of CDNs for anti‐tumor immunity, providing a practical approach to enhance cancer immunotherapy.