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

## TL;DR

This paper explores how attaching folic acid to siRNA at a specific location improves its delivery into cancer cells that have a folate receptor.

## Contribution

The study introduces a novel siRNA design with 3′ terminal conjugation that enhances cellular accumulation and gene silencing in FOLR1-expressing cells.

## Key findings

- Conjugating a substituent at the 3′ end of the antisense strand improves siRNA stability and intracellular accumulation.
- The modified FA–siRNA format shows enhanced gene knockdown in cells expressing folate receptor 1.
- This approach offers a promising strategy for targeted gene silencing in folate receptor-positive tumors.

## Abstract

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.