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

Abstract 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.