Virus-like Nanoparticles Deliver Small Interfering RNA to Pancreatic Cancer Cells through Filopodia-Mediated...

Area of Science:

• Biotechnology
• Nanomedicine
• Cancer Therapeutics

Background:

• Efficient delivery of small interfering RNA (siRNA) to solid tumors is a significant hurdle for RNA interference (RNAi) therapies.
• Current methods face challenges with inefficient cellular uptake and off-target toxicity.

Purpose of the Study:

• To develop a virus-inspired peptide-based virus-like nanoparticle (pVLP) system for enhanced siRNA delivery to solid tumors.
• To improve tumor cell-specific targeting and intracellular transfection efficiency.

Main Methods:

• Engineered pVLPs with tumor-targeting peptides (EphA2, CD13), a self-assembling peptide, and an arginine-rich peptide for siRNA encapsulation.
• Investigated pVLP-induced filopodia formation and its impact on cellular uptake.
• Evaluated in vitro gene silencing of signal transducer and activator of transcription 3 (STAT3) and in vivo efficacy in an orthotopic pancreatic cancer model.

Main Results:

• pVLP system significantly enhanced cellular uptake (10.9-fold increase) via filopodia induction.
• Achieved >90% STAT3 gene silencing in vitro with high tumor cell selectivity (selectivity ratio 4.5).
• In vivo, pVLPs reduced STAT3 mRNA expression 3.7-fold more than MC3 LNPs, leading to 91.6% mRNA degradation. Combination therapy showed synergistic tumor growth suppression (up to 87%).

Conclusions:

• The peptide-based virus-like nanoparticle (pVLP) system effectively overcomes siRNA delivery challenges in solid tumors.
• This virus-inspired strategy demonstrates significant potential for clinical translation in RNAi-based cancer therapeutics.