Multiprotein Silencing Using WRAP-Based Nanoparticles: A Proof of Concept

Abstract

Cancer remains the leading cause of death, with chemotherapy, radiotherapy, and surgical resection being the primary treatment methods. However, chemotherapy’s side effects, surgical limitations, and drug resistance present significant challenges. Small interfering RNA (siRNA) has emerged as a promising tool in cancer therapy due to its ability to silence disease-related genes selectively. Recent advancements in nonviral delivery systems, particularly cell-penetrating peptides (CPPs), have enhanced the efficacy of siRNA delivery. The use of siRNA as a therapeutic tool in cancer treatment has been reported in the literature. However, silencing only one target protein has only a minor effect on tumor cell proliferation, as previously shown for WRAP-based nanoparticles targeting cyclin-dependent kinase 4 (CDK4) in human U87 glioblastoma cells. Here, we designed a more sophisticated approach to enhance therapeutic efficacy, encapsulating multiple siRNAs targeting CDK4, cyclin D1 (CD1), and MCL-1 proteins. The siRNA cocktail, delivered via WRAP5 nanoparticles, effectively silenced these targets and reduced cell proliferation in human U87 glioblastoma cells. Furthermore, the nanoparticles also demonstrated potential therapeutic impact in gastrointestinal stromal tumors (GIST), a rare cancer characterized by its tendency to resist standard treatments. This study highlights the versatility of WRAP5 nanoparticles as a platform for personalized cancer therapy, suggesting that siRNA delivery systems may be tailored to specific cancer types for more effective treatment strategies.