Tumor suppressor protein-inspired peptide for siRNA delivery and synergistic cancer therapy

Area of Science:

• Biotechnology
• Nanomedicine
• Molecular Biology

Background:

• Small interfering RNA (siRNA) therapeutics face challenges with cellular uptake and endosomal escape.
• Effective delivery vectors are crucial for RNA interference (RNAi) technology's clinical application.

Purpose of the Study:

• To develop a self-assembled nanoparticle for efficient siRNA delivery targeting polo-like kinase 1 (PLK1).
• To investigate the dual-action therapeutic potential of targeting both G1 and G2 cell cycle phases for cancer treatment.

Main Methods:

• Design of a functional polypeptide nanoparticle integrating cell membrane-penetrating peptide (CPP44) and p16 minimal inhibitory sequence (p16MIS).
• Delivery of siRNA targeting PLK1 (siPLK1) using the designed peptide nanoparticles.
• In vitro and in vivo evaluation of nanoparticle efficacy, including gene silencing, cell cycle arrest, apoptosis induction, and antitumor activity.

Main Results:

• The peptide nanoparticle effectively mediated siRNA endocytosis and endosomal escape.
• Co-delivery of siPLK1 and p16MIS demonstrated synergistic tumor cell apoptosis and inhibition.
• Demonstrated high gene silencing efficiency, significant antitumor activity, and therapeutic efficacy in vitro and in vivo.

Conclusions:

• Developed peptide nanoparticles offer a novel strategy for cancer treatment by simultaneously targeting multiple cell division stages.
• This approach enhances therapeutic efficacy by combining PLK1 gene silencing with p16MIS-mediated cell cycle inhibition and apoptosis induction.