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(s)A(s)MP) to dendritic cells (DCs) and induce cell activation. These LNPs are highly reproducible, effectively encapsulate cG(s)A(s)MP, and are easily scalable. We show that cG(s)A(s)MP LNPs are efficiently internalized by DCs in vitro, and the cargo is released into the cytoplasm, which strongly enhances STING activation and DC maturation. Furthermore, we introduce an in vitro model of tumor-associated human DCs that mimics the DC phenotype observed in cancer patients. When applied to this model, cG(s)A(s)MP 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.