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Chem. Eng. J., Volume 500, 15 November 2024, 157037 | https://doi.org/10.1016/j.cej.2024.157037
Assembly of 2′,3′-Cyclic guanosine Monophosphate-Adenosine monophosphate and their spontaneous intracellular disassembly for enhanced antitumor immunity via natural STING pathway activation
Jung Yeon Park a,1, Miso Kang b,1, Songhyun Lim b,1, Hyejin Cho b, Seoyeong Yang c,d, Soo Yeon Baek b, Linfeng Tan e, Chiman Song c,f, Myongsoo Lee e, Bongjun Yeom g, Jeong Sook Ha h, Sanghee Lee b,i, Yongju Kim a,c,j
aKU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea
bBrain Disorders Research Center, Brain Science Research Division, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
cChemical and Biological Integrative Research Center, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
dCollege of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
eDepartment of Chemistry, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Fudan University, Shanghai, China
fDivision of Bio-Medical Science & Technology, KIST School, University of Science and Technology, Seoul 02792, Republic of Korea
gDepartment of Chemical Engineering, Hanyang University, Seoul 24763, Republic of Korea
hDepartment of Chemical and Biological Engineering, Korea University, Seoul 02841, Republic of Korea
iKHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea
jDepartment of Integrative Energy Engineering, Korea University, Seoul 02841, Republic of Korea
1These authors contributed equally to this work.
Corresponding authors: Sanghee Lee, Yongju Kim
aKU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea
bBrain Disorders Research Center, Brain Science Research Division, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
cChemical and Biological Integrative Research Center, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
dCollege of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
eDepartment of Chemistry, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Fudan University, Shanghai, China
fDivision of Bio-Medical Science & Technology, KIST School, University of Science and Technology, Seoul 02792, Republic of Korea
gDepartment of Chemical Engineering, Hanyang University, Seoul 24763, Republic of Korea
hDepartment of Chemical and Biological Engineering, Korea University, Seoul 02841, Republic of Korea
iKHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea
jDepartment of Integrative Energy Engineering, Korea University, Seoul 02841, Republic of Korea
1These authors contributed equally to this work.
Corresponding authors: Sanghee Lee, Yongju Kim
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.
논문정보
- Research article
- 2024년 11월 (BRIC 등록일 2024-11-20)
- 국내(교신)+국외 연구진
- 바이오·의료융합 > 바이오소재
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