Simultaneous dual-membrane protein degradation using bivalent aptamer-delivered lysosome-targeting chimeras

Diseases often involve multiple abnormal proteins, and degrading them simultaneously is a promising therapeutic strategy. However, transitional lysosome-targeted chimeras (LYTACs) with dedicated delivery modules typically degrade only one protein. Adding more protein of interest (POI)-targeting modules to degrade multiple targets would increase the molecular weight, leading to higher doses and side effects. Here, we report a bivalent aptamer-based delivery system for LYTAC (BideTAC), which leverages the aptamer itself as a dual-function module for targeting and delivery, eliminating the need for a dedicated delivery module and effectively reducing the molecular weight. As a proof of concept, we designed a specific BideTAC (AptHP) to simultaneously degrade PD-L1 and HER2 by conjugating anti-PD-L1 antagonistic aptamer and anti-HER2 aptamer. AptHP effectively degrades two proteins simultaneously, enhancing the therapeutic effect. Therefore, BideTAC provides a potent tool for multiple protein degradation, opening an avenue to push aptamer-based LYTAC toward applications in synergistic therapy.