Bifunctional Silk Nanospheres for Targeted Delivery of Oligonucleotide Therapeutics to VEGFR-Positive Cells in the Tumor Microenvironment

Small interfering RNAs (siRNAs) offer considerable promise as anticancer therapeutics because they enable the precise silencing of disease-related gene expression. However, its clinical potential is limited by rapid degradation and possible off-target toxicity, necessitating the development of an effective targeted delivery system. Bioengineered silk, a biocompatible and biodegradable material, can be tailored with functional peptides to enable nucleic acid binding and receptor-specific targeting. We developed five MS1 silk-based proteins that target VEGFR-1 or VEGFR-2, which are receptors that are frequently overexpressed in the tumor microenvironment (TME), including both endothelial and cancer cells. These were blended with MS2KN silk, which binds nucleic acids, to generate hybrid nanospheres. The resulting carriers exhibited high siRNA loading efficiency, selective binding to VEGFR-overexpressing endothelial and nonsmall cell lung cancer (NSCLC) cells, and efficient cellular uptake. Delivery of siRNA via these nanospheres led to a significant reduction in target gene expression. Our platform has strong potential for targeted siRNA delivery to VEGFR-overexpressing cells within the TME.