Tetrahedral Deoxyribonucleic Acid-Engineered Multivalent Lysosome-Targeting Chimera for Enhanced and Dual Membrane Protein Degradation.

The lysosome-targeting chimera (LYTAC) approach, especially aptamer-based LYTAC, has shown promise for the targeted degradation of secreted and membrane proteins. However, the conventional monovalent aptamer-based LYTAC has limited degradation efficiency, due to poor cellular internalization and limited serum stability. Herein, we developed a tetrahedral DNA and aptamer-based multivalent lysosome targeting chimera (TDA-MLYTAC) for targeted degradation of single or dual protein targets. Benefiting from the properties of tetrahedral DNA, TDA-MLYTAC demonstrates significant improvement in cellular uptake, precise target identification, and cellular stability. Our study proved that TDA-MLYTAC modified with trivalent triantenerrary N-acetylgalactosamine and monovalent aptamer induced liver-cell specific degradation of membrane proteins twice as efficiently as the monovalent aptamer-based LYTAC through the lysosomal pathway. The bispecific TDA-MLYTAC modified with two aptamers has great potential for inducing dual-targeted protein degradation. By rationally designing the recognition elements for receptors and proteins, it is possible to revolutionize the development of targeted protein degradation tools and lay the groundwork for receptor-mediated drug therapies.