# Chemically inducible antisense oligonucleotides for cell-specific gene silencing

## TL;DR

Scientists created a new type of antisense oligonucleotides that only work in tumor cells, reducing side effects in normal cells.

## Contribution

A novel class of chemically inducible ASOs was developed for tumor-cell-specific gene silencing.

## Key findings

- iASOs showed minimal gene silencing in normal cells but over 80% knockdown in tumor cells.
- The iASOs effectively targeted the Bcl2 gene and induced cell death in tumor cells.
- The platform enables conditional gene regulation and cell-specific ASO therapeutics.

## Abstract

Cell-specific control of the function of antisense oligonucleotides (ASOs) is highly desirable for precise gene therapy while minimizing adverse effects in normal cells. Herein, we report a novel class of chemically inducible ASOs (iASOs) that achieve tumor-cell-selective gene silencing through hydrogen peroxide (H2O2)-triggered activation. Through post-synthetic incorporation of phenylboronic acid (BO) caging groups at the backbone positions, we developed iASOs that remain functionally inactive until the H2O2-triggered removal of the BO groups caused activation. Using EGFP as a reporter system, we demonstrated that the optimal BO-modified iASO exhibited slight gene silencing activity in normal cells but achieved >80% knockdown of the target mRNA in tumor cells. The BO-modified iASO was further applied to target the endogenous Bcl2 gene, demonstrating its ability for controlling gene silencing and inducing cell death. This study establishes a simple and effective platform for conditional gene regulation and the development of cell-specific ASO therapeutics.

Chemically inducible antisense oligonucleotides (iASOs) have been developed by site-specific incorporation of phenylboronic acid (BO) groups at backbone positions, thereby enabling precise and controllable gene silencing in live cells.