查看文章

Stimulator of interferon genes, namely STING, an adaptor protein located in the endoplasmic reticulum, has been recognized as a shining target for cancer and infection research. However, STING agonists cyclic dinucleotides (CDNs) have shown almost zero efficacy in phase I clinical trials as a monotherapy, likely due to poor cellular permeability and rapid diffusion despite intratumoral injection. These deficiencies further affect other applications of CDNs, such as pandemic SARS-CoV-2 prevention and therapy. Here, we rationally design a supramolecular cytosolic delivery system based on controllable recognition of calixarene, namely CASTING (CAlixarene-STING), to improve CDN druggability, including degradation stability, cellular permeability, and tissue retention. CASTING efficiently enhances the immunostimulatory potency of CDG^SF [a chemically modified cyclic di-GMP (CDG)] to generate an …