Loading of STING Agonist into Lipid Nanoparticles Boosts Dendritic Cell Activation

Activation of the STING pathway is crucial for antitumor immunity, but targeting the STING receptor therapeutically remains a challenge due to inefficient intracellular delivery of its agonists. Here, we explore the potential of FDA-approved lipid nanoparticles (LNPs), used in Spikevax COVID-19 vaccine, to increase the uptake of a cGAMP analog (cG^sA^sMP) to dendritic cells (DCs) and induce cell activation. These LNPs are highly reproducible, effectively encapsulate cG^sA^sMP, and are easily scalable. We show that cG^sA^sMP LNPs are efficiently internalized by DCs <i>in vitro</i>, and the cargo is released into the cytoplasm, which strongly enhances STING activation and DC maturation. Furthermore, we introduce an <i>in vitro</i> model of tumor-associated human DCs that mimics the DC phenotype observed in cancer patients. When applied to this model, cG^sA^sMP LNPs successfully reprogram tumor-associated DCs toward an active state, thus emphasizing their potential for cancer immunotherapy. Overall, this work presents a novel and scalable approach utilizing LNPs to deliver cyclic dinucleotide-based STING agonists to counteract immune suppression in cancer.