Supramolecular Cyclic Dinucleotide Nanoparticles for STING-Mediated Cancer Immunotherapy

Authors：Xu, Li; Deng, Hongping; Wu, Liang; Wang, Dali; Shi, Leilei; Qian, Qiuhui; Huang, Xiangang; Zhu, Lijuan; Gao, Xihui; Yang, Jiapei; Su, Yue^*; Feng, Jing^*; Zhu, Xinyuan^*

Source：ACS Nano, 2023, 17(11): 10090-10103.

DOI：10.1021/acsnano.2c12685

• STING
• Cyclic dinucleotides
• Supramolecularnanodrug delivery systems
• Tumor microenvironment reprogramming
• Cancer immunotherapy

Activation of stimulator of interferon genes (STING)can reprogramthe immunosuppressive tumor microenvironment (TME) by initiating innateand adaptive immunity. As natural STING agonists, clinical translationof cyclic dinucleotides (CDNs) has been challenged by their shorthalf-life in circulation, poor stability, and low membrane permeability.Herein, we use the natural endogenous small molecules oleic acid anddeoxycytidine to construct a ligand for the STING agonist c-di-GMP(CDG), a hydrophobic nucleotide lipid (3 ',5 '-diOA-dC),which can assemble with CDG into stable cyclic dinucleotide nanoparticles(CDG-NPs) through various supramolecular forces driven by molecularrecognition. CDG-NPs are homogeneous and stable spherical nanoparticleswith an average diameter of 59.0 +/- 13.0 nm. Compared with freeCDG, CDG-NPs promote the retention and intracellular delivery of CDGin the tumor site, boost STING activation and TME immunogenicity,and potentiate STING-mediated anti-tumor immunity when administeredby either intratumoral or systemic routes in melanoma-bearing mice.We propose a flexible supramolecular nanodelivery system for CDG byusing endogenous small molecules, which provides a CDN delivery platformfor STING-mediated cancer immunotherapy.

• Institution
  南方医科大学; y; 上海交通大学