Precision delivery of RAS-inhibiting siRNA to KRAS driven cancer via peptide-based nanoparticles

Area of Science:

• Oncology
• Nanotechnology
• Molecular Biology

Background:

• KRAS activation drives over 95% of pancreatic ductal adenocarcinomas (PDAC) and other cancers, but lacks direct inhibitors.
• Pancreatic tumors present significant drug delivery challenges due to dense desmoplasia.
• Small interfering RNA (siRNA) offers targeted anti-cancer therapy but faces limitations in stability and delivery.

Purpose of the Study:

• To evaluate a peptide-based nanoparticle (NP) system for delivering siRNA to KRAS-driven cancers.
• To assess the efficacy of this NP system in inhibiting KRAS expression and pancreatic cancer growth both in vitro and in vivo.

Main Methods:

• Development of a peptide-based, oligonucleotide condensing, endosomolytic nanoparticle system.
• In vitro studies assessing NP uptake, KRAS-specific siRNA delivery, KRAS expression inhibition, and cancer cell viability.
• In vivo studies in a spontaneous KPPC model of PDAC to evaluate siRNA delivery to the tumor microenvironment, KRAS expression reduction, and tumor growth inhibition.

Main Results:

• The peptide-based NP system demonstrated avid uptake by cancer cells in vitro.
• Successful delivery of KRAS-specific siRNA resulted in KRAS expression inhibition and reduced cancer cell viability.
• In vivo studies showed effective siRNA delivery to the tumor microenvironment, reduced KRAS expression, and inhibited pancreatic cancer growth in a stroma-rich PDAC model.

Conclusions:

• The developed nanoparticle system effectively delivers siRNA to KRAS-driven tumors, including challenging pancreatic cancers.
• This therapeutic strategy shows promise for overcoming drug delivery barriers and inhibiting tumor progression in KRAS-mutated solid tumors.
• The findings suggest potential translational relevance for patients with KRAS-driven cancers.