Tumor-responsive covalent organic polymeric nanoparticles enhancing STING activation for cancer immunotherapy

The cyclic guanosine monophosphate-adenosine monophosphate synthase and the stimulator of interferon genes (cGAS-STING) has emerged as a promising target for cancer immunotherapy. However, the development of natural STING agonists is impeded by several challenges, including limited biostability, poor pharmacokinetics, and inefficient cytosolic delivery. Herein, we meticulously designed a double- layer polyethylenimine (PEI) modified nanoscale covalent organic polymer (CPGP) for efficient delivery of 2 ' 3' cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), a natural STING agonist. The double-layer PEI structured CPGP enhanced both the loading capacity and stability of cGAMP. Furthermore, CPGP improved the intracellular delivery efficiency and amplified the activation of STING pathway for the secretion of type-I interferon and pro-inflammatory cytokines. In contrast, single-layered nanoparticles failed to permit stable loading and intracellular delivery of cGAMP for immune response. The nano-STING agonist also mitigated the immunosuppressive tumor microenvironment (TME) by reducing regulatory T cells and polarizing M2 macrophages to the M1 phenotype, thereby creating an immune-supportive TME to enhance adaptive immune responses. The combination of CPGP and immune checkpoint blockers showed synergistic effect, further enhancing the inhibition effect on tumor growth. This double-layer PEI modified CPGP may offer a generalizable platform for other natural dinucleotide STING agonists to overcome the cascade delivery barriers, augmenting immune activation for tumor immunotherapy. (c) 2025 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.