Expression of a RAS Degrader via Synthetic Nanocarrier-Mediated mRNA Delivery Reduces Pancreatic Tumors

Therapeutic gene expression can address many of the challenges associated with the controlled delivery of intracellularly active biologics, such as enzymes that degrade RAS for the treatment of RAS-driven cancers. Here, we demonstrate that an optimized synthetic nonviral gene delivery platform composed of poly(ethylene glycol)-<i>b</i>-poly(propylene sulfide) (PEG-PPS) can block copolymers conjugated to a dendritic cationic peptide (PPDP2) for nontoxic delivery and therapeutic expression of mRNA within human pancreatic cancer cells and tumors. The naturally occurring bacterial enzyme RAS/RAP1-specific endopeptidase (RRSP) is a potent RAS degrader that specifically targets all RAS isoforms. Using PPDP2, <i>rrsp</i>-mRNA is delivered to human pancreatic cells, resulting in RRSP protein expression, degradation of RAS, and loss of cell proliferation. Further, pancreatic tumors are reduced with residual tumors lacking detectable RAS and phosphorylated ERK. Using structural modeling, we further demonstrate that a noncatalytic RAS-binding domain of RRSP provides high specificity for RAS. These data support the notion that the synthetic nanocarrier PPDP2 can deliver <i>rrsp</i>-mRNA to pancreatic tumor cells to interrupt the RAS signaling system.