Assembly of 2′,3′-Cyclic guanosine Monophosphate-Adenosine monophosphate and their spontaneous intracellular disassembly for enhanced antitumor immunity via natural STING pathway activation

Authors
Park, Jung YeonKang, MisoLim, SonghyunCho, HyejinYang, SeoyeongBaek, Soo YeonTan, LinfengSong, ChimanLee, MyongsooYeom, BongjunHa, Jeong SookLee, Sang heeKim, Yongju
Issue Date
2024-11
Publisher
Elsevier BV
Citation
Chemical Engineering Journal, v.500
Abstract
The stimulator of interferon genes (STING) pathway plays an important role in remodeling the immunosuppressive tumor microenvironment (TME). Cyclic dinucleotides (CDNs), the natural ligands of STING, activate innate immunity to enhance tumor immunogenicity. However, the anionic properties of CDNs result in poor membrane permeability, while their rapid metabolism by enzymes hinders the efficient targeting and activation of STING in vitro and in vivo. To improve the bioavailability and antitumor immunity of CDNs, we designed a hydrogen-bonding-based supramolecular approach for 2′,3′-cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP). Leveraging the synthetic molecules cytosine-uracil-hexane (CUH), we formulated supramolecular micelles of cGAMP via specific hydrogen bonds in aqueous solutions. Micelles comprising the CUH-cGAMP complex enhanced the biological efficacy of cGAMP by increasing its stability, thereby prolonging the activation of STING-mediated innate and adaptive immunity. We demonstrated that CUH-cGAMP stands as a promising candidate for immunotherapy, exhibiting significant inhibition of tumor growth in a CT26 syngeneic mouse model.
ISSN
1385-8947
URI
https://pubs.kist.re.kr/handle/201004/150959
DOI
10.1016/j.cej.2024.157037
Appears in Collections:
KIST Article > 2024
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