Synthetic High‐Density Lipoprotein Mimicking Nanodiscs with Pt(IV) Prodrug Enable Tumor Targeting and cGAS‐STING Pathway Activation for Chemo‐Immunotherapy

Cisplatin is a first-line, broad-spectrum anti-tumor drug used to treat various types of cancer. However, immune-suppressive tumor microenvironments (TME) are often induced by cisplatin. Here, a first synthetic high-density lipoprotein (sHDL) nanodisc, referred as sHDL@Pt, is engineered to load a Pt(IV) prodrug (C2-Pt(IV)-C12), inducing a 2.2-fold increase in dsDNA release compared to cisplatin. This further activates the innate immune system through the cGAS-STING pathway. Using near-infrared II fluorescence imaging and single photon emission computed tomography imaging technology, it is found that sHDL@Pt can be effectively accumulated in tumor sites. The sHDL@Pt can induce severe DNA damage, which subsequently results in a more pronounced activation of the cGAS-STING pathway, further promoting dendritic cell maturation and T cell proliferation, triggering strong cytotoxic T lymphocyte responses, and inhibiting tumor growth. This work introduces a novel approach for delivering Pt(IV) prodrug that effectively initiates and activates innate immunity through the activation of the cGAS-STING pathway.