Lanthanide-Nucleotide Coordination Nanoparticles for STING Activation

Activation of the stimulator of interferon genes (STING) is essential for blocking viral infections and eliciting antitumor immune responses. Local injection of synthetic STING agonists, such as 2'3'-cGAMP [cGAMP = cyclic 5'-guanosine monophosphate (cGMP)-adenosine monophosphate (AMP)], is a promising approach to enhance antiviral functions and cancer immunotherapy. However, the application of such agonists has been hindered by complicated synthetic procedures, high doses, and unsatisfactory systemic immune responses. Herein, we report the design and synthesis of a series of 2'3'-cGAMP surrogates in nanoparticle formulations formed by reactions of AMP, GMP, and coordinating lanthanides. These nanoparticles can stimulate the type-I interferon (IFN) response in both mouse macrophages and human monocytes. We further demonstrate that the use of europium-based nanoparticles as STING-targeted adjuvants significantly promotes the maturation of mouse bone-marrow-derived dendritic cells and major histocompatibility complex class I antigen presentation. Dynamic molecular docking analysis revealed that these nanoparticles bind with high affinity to mouse STING and human STING. Compared with soluble ovalbumin (OVA), subcutaneously immunized europium-based nanovaccines exhibit significantly increased production of primary and secondary anti-OVA antibodies (∼180-fold) in serum, as well as IL-5 (∼28-fold), IFN-γ (∼27-fold), and IFN-α/β (∼4-fold) in splenocytes ex vivo. Compared with the 2'3'-cGAMP/OVA formulation, subcutaneous administration of nanovaccines significantly inhibits B16F10-OVA tumor growth and prolongs the survival of tumor-bearing mice in both therapeutic and protective models. Given the rich supramolecular chemistry with lanthanides, this work will enable a readily accessible platform for potent humoral and cellular immunity while opening new avenues for cost-effective, highly efficient therapeutic delivery of STING agonists.