Improving the Cellular Accumulation of Folate-Conjugated Fully Chemically Modified siRNAs via 3' Terminal Conjugation

Folic acid (FA) conjugation is a validated tumor-specific delivery platform for small molecules. Although targeted delivery using FA-conjugated oligonucleotides, such as microRNA and small interfering RNAs (siRNA), has been reported, the performance of FA-conjugated fully chemically modified siRNAa commonly used siRNA platform in clinical studiesremains unclear. To enhance the cellular accumulation of siRNA and subsequent gene knockdown (KD), we designed various FA-siRNA-based formats and evaluated their performance in folate receptor 1 (FOLR1)-expressing cells. Intracellular accumulation was enhanced by the conjugation of a substituent at the 3' end of the antisense strand in FA-siRNA, which potentially stabilized the siRNA. Our study presents a promising approach for enhancing gene silencing in FOLR1-expressing cells.