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Stimulus-activated ribonuclease targeting chimeras for tumor microenvironment activated cancer therapy
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Journal Article
Stimulus-activated ribonuclease targeting chimeras for tumor microenvironment activated cancer therapy
2025
Overview
RNA degradation using ribonuclease targeting chimeras (RiboTACs) is a promising approach for cancer therapy. However, potential off-target degradation is a serious issue. Here, a RiboTAC is designed for tumor microenvironment triggered activation. The tumor microenvironment activated RiboTAC (TaRiboTAC) incorporates two pre-miR-21 binders, a near-infrared fluorophore IR780, an RGD targeting peptide and a phenylboronic acid caged ribonuclease recruiter. The caged ribonuclease recruiter is embedded in the molecule and exposed in acidic pH, the phenylboronic acid cage is removed by H
2
O
2
making the TaRiboTAC responsive to the acidic and high H
2
O
2
levels in the tumor microenvironment. It is shown the TaRiboTAC targets tumor tissue and degrades pre-miR-21. The degradation of pre-miR-21 by TaRiboTACs significantly increases the radiotherapeutic susceptibility of cancer cells achieving efficient suppression of human lung adenocarcinoma A549 tumors in living mice.
Off-target effects have limited RNA degradation approaches. Here, the authors develop a tumor microenvironment-activated ribonuclease targeting chimera (RiboTAC) demonstrating H
2
O
2
and acid activated degradation of pre-miR-21, which was effective in restoring radiosensitivity in lung cancer.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
