Amplifying the Antitumor Effect of STING Agonist MSA-2 by Phospholipid Nanoparticles Delivering STING mRNA and Copper-Modified MSA-2 Combination

STING activation is a promising application therapeutic strategy for cancer immunotherapy. In particular, MSA-2 as an oral STING agonist is discovered to have antitumor activity. However, how to improve the antitumor effect of MSA-2 is a very valuable contribution to cancer immunotherapy. Here, we use two strategies to amplify the antitumor effect of MSA-2 by phospholipid nanoparticles delivering STING mRNA and copper-modified MSA-2. We synthesized a new series of ionizable phospholipid nanoparticles and optimized a phospholipid nanoparticle (1AP24) for delivering STING mRNA, increasing the expression of STING protein to bind more MSA-2. Second, we synthesized copper-modified MSA-2 (MSA-2-Cu), which induced cell death by Cu²⁺ toxicity. Combining 1AP24@STING mRNA and MSA-2-Cu can crucially decrease tumor growth and increase a mouse's survival. It is a new treatment strategy through amplifying the STING pathway.