Supramolecular Cyclic Dinucleotide Nanoparticles for STING-Mediated Cancer Immunotherapy

Abstract

Activation of stimulator of interferon genes (STING) can reprogram the immunosuppressive tumor microenvironment (TME) by initiating innate and adaptive immunity. As natural STING agonists, clinical translation of cyclic dinucleotides (CDNs) has been challenged by their short half-life in circulation, poor stability, and low membrane permeability. Herein, we use the natural endogenous small molecules oleic acid and deoxycytidine 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 molecular recognition. CDG-NPs are homogeneous and stable spherical nanoparticles with an average diameter of 59.0 ± 13.0 nm. Compared with free CDG, CDG-NPs promote the retention and intracellular delivery of CDG in the tumor site, boost STING activation and TME immunogenicity, and potentiate STING-mediated anti-tumor immunity when administered by either intratumoral or systemic routes in melanoma-bearing mice. We propose a flexible supramolecular nanodelivery system for CDG by using endogenous small molecules, which provides a CDN delivery platform for STING-mediated cancer immunotherapy.

In Situ Sprayed Exosome-Cross-Linked Gel as Artificial Lymph Nodes for Postoperative Glioblastoma Immunotherapy

“…As a class of anionic, highly water-soluble molecules, cGAMP cannot readily cross cell membranes and is therefore inaccessible to STING recognition receptors in the cytoplasm. 44,45 In this context, cGAMP molecules were the preferred adjuvant loaded into chimeric exosomes to obtain optimized bALG@DT-Exo gels with STING-activating performance (bALG@DT-Exo-STING). The loading of fluorescently labeled STING agonists (cdGMP-Dy547) into chimeric exosomes using electroporation was certified to be feasible (Figure S15), and there were no obvious differences in the encapsulation efficiencies of these STING agonists in DT-Exos and N 3 -DT-Exos (Figure S16).…”

“…2′3′-Cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), a frequently used agonist of STING pathway, can elicit a robust immunoinflammatory program that contributes to APC activation for the succeeding priming of antitumor T-cell immunity via the cytosolic pattern-recognition receptor. − Although encouraging, the clinical application of cGAMP molecules has yet to be advanced owing to their poor drug-like property. As a class of anionic, highly water-soluble molecules, cGAMP cannot readily cross cell membranes and is therefore inaccessible to STING recognition receptors in the cytoplasm. , In this context, cGAMP molecules were the preferred adjuvant loaded into chimeric exosomes to obtain optimized bALG@DT-Exo gels with STING-activating performance (bALG@DT-Exo-STING). The loading of fluorescently labeled STING agonists (cdGMP-Dy547) into chimeric exosomes using electroporation was certified to be feasible (Figure S15), and there were no obvious differences in the encapsulation efficiencies of these STING agonists in DT-Exos and N 3 -DT-Exos (Figure S16).…”

Nanomaterial-encapsulated STING agonists for immune modulation in cancer therapy

“…Considering the biosafety, 3′,5′-diOA-dC can be metabolized to relatively safe ingredients, such as oleic acid and deoxycytidine, in vivo. Compared to free CDG, supramolecular CDG-NPs also showed increased accumulation and retention of CDG in murine melanoma tumor tissues, accompanied by increased secretion of type I IFNs [ 95 ]. Furthermore, extracellular vehicles (EVs) have been identified as natural NPs separated by lipid bilayers secreted from various cells, with favorable biocompatibility for drug delivery [ 96 ].…”

“…Firstly, the potential toxicity and side effects might be raised from the nanocarriers of STING-NPs, such as cationic materials or metal-based architectures. The interactions between these nanocarriers and physiological tissues may cause unwanted outcomes, such as formation of thrombi, cytotoxicity, and genotoxicity [ 95 , 156 , 157 ]. Secondly, NPs stability can be affected by biomolecules and components suspended in circulation.…”

At the Crossroads of the cGAS-cGAMP-STING Pathway and the DNA Damage Response: Implications for Cancer Progression and Treatment

“…cGAMP and analogs work much better when they are aided by smart delivery vehicles. Since there are excellent recent reviews on this subject [211,212], we mention only that among recent breakthroughs and improvements using these approaches, the most interesting include polymerosomes made with matryoshka layers, CDN encapsulated with polyethylenimine (PEI), biodegradable disulfide cross-lined with polycarbonate and covered with polyethylene glycol (PEG) [213] so that it should unfold in the cytoplasm, polymerosomes [214], and stable cyclic dinucleotide nanoparticles with a hydrophobic nucleotide lipid (3 ,5 -di(oleoyl-deoxycytidine) [215].…”