Reprogramming the Tolerogenic Immune Response Against Pancreatic Cancer Metastases by Lipid Nanoparticles Delivering a STING Agonist Plus Mutant KRAS mRNA.

ABSTRACT: We demonstrate reprogramming of the tolerogenic immune environment in the liver for mounting an effective immune response against often-fatal pancreatic cancer metastases. This was achieved by engineering a lipid nanoparticle (LNP) to deliver mRNA encoding the KRAS G12D neoantigenic epitope along with cGAMP, a dinucleotide agonist of the stimulator of the interferon genes (STING) pathway, capable of activating a type I interferon response. cGAMP/mKRAS/LNP were synthesized by a microfluidics approach involving nanoprecipitation of mRNA and cGAMP by an ionizable lipid, MC3. Controls included nanoparticles delivering individual components or a wild-type RAS sequence. The dual delivery carrier successfully activated the type I interferon pathway in vitro as well as in vivo, with

SUBMITTER: Xu X 

PROVIDER: S-EPMC11912578 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature