Branched DNA Nanoplatform-Based Multivalent PROTACs for Tumor Microenvironment-Responsive Degradation of Telomere-Binding Proteins in Tumor Therapy.

Targeted protein degradation systems have been widely employed in biomedical applications. Herein, we report a branched DNA nanoplatform-based multivalent proteolysis-targeting chimera (PROTAC) for efficient degradation of telomeric repeat-binding factor proteins (TRF1/2) in vivo. In our design, a branched DNA-based scaffold with predesigned numbers of PROTACs utilizing telomere mimics as warheads can be synthesized to coassemble with pro-melittins for efficient Legumain-responsive intratumoral permeation. After cellular uptake, the protein degradation units can be subsequently released by GSH reduction to recruit their target proteins (TRF1/2) and key E3 ligases. Owing to covalent characteristics and optimized spatial positions, the branched PROTACs can achieve a multivalent cooperative effect to enhance their degradation efficiency and trigger a series of subsequent cellular behaviors for tumor therapy while showing minimal side effects on normal cells. This tailored targeted protein degradation system based on a branched DNA nanoplatform presents a new avenue for development of precise therapy.