Cyclic Dinucleotide Self-Assembled Nanoparticles as a Carrier-Free Delivery Platform for STING-Mediated Cancer Immunotherapy

Cyclic dinucleotides (CDNs) are natural agonists of the stimulator of interferon genes (STING), which is an attractive immunotherapy target. Currently, CDNs , their derivatives are being investigated clinically. However, the poor bioavailability of exog-enous CDNs has limited their application in immu-notherapy. Although nanocarriers are widely used for cytosolic delivery of CDNs, their loading capaci-ty is insufficient , their complicated composition and purification process raises bio-compatibility concerns. Herein, we report a super-simplified CDN self-assembly strategy for carrier-free delivery of CDNs. In the presence of excess K+, CDNs form oligomers which further self-assemble with divalent metal ions (such as Mn2+) to form nanoparticles (NPs) in aqueous solution. We demonstrate that the self-assembled CDN NPs promote cellular uptake of CDNs and enhance tumor immunogenicity by remodeling the tumor microenvironment, inducing immunogenic tumor cell death and increasing tumor -infiltrating lymphocytes, which is conducive to the generation of tumor neoantigen-specific T-cell res-ponses. We also demonstrate that the use of CDN NPs alone or in combination with immune checkpoint blockades inhibits tumor growth, highlighting the fact that CDN NPs are a potent platform for cancer immunotherapy.