Delivery of Stimulator of Interferon Genes (STING) Agonist Using Polypeptide?Modified Dendrimer Nanoparticles in the Treatment of Melanoma

The activation of stimulator interferon genes (STING) in the cytosol by cyclic dinucleotides (CDNs) enhances antitumor immunity through induction proinflammatory cytokines, such as type-I interferons (IFN-I). However, high hydrophilicity and negative charge CDNs hinders their delivery into cells. Here, developing a library cationic polypeptide-modified dendrimers, it is shown that can be efficiently delivered intracellularly vitro vivo. With respect to naked generation-5 polyamidoamine (G5-PAMAM) dendrimers modified with arginine or mixture arginine/lysine polypeptides affords higher CDN-packaging capacity leads IFN-I nuclear factor kappa-light-chain-enhancer activated B cells (NF-?B) signaling pathway. In B16-F10 murine model melanoma, intratumoral administration synthetic CDN via arginine-modified G5-PAMAM at low dose induces strong responses inhibits tumor growth. It also combination this therapy immune checkpoint blockade (ICB) further improves therapeutic outcomes. Cationic polypeptide may advantageous gene-based immunomodulators for treatment solid tumors.