Modular Lysosome-Targeting Platform Based on a Multivalent DNA Framework for Programmable Protein Degradation

Abstract Targeted degradation of extracellular and membrane-bound proteins holds immense therapeutic potential but remains technically challenging. Lysosome-targeting chimeras (LYTACs) have emerged to bridge this gap, yet platforms built on monomeric aptamers suffer from inadequate stability, inefficient cellular uptake, and a lack of modularity. Here, we developed a tetrahedral DNA nanostructure-based multivalent lysosome-targeting antibody platform (TDN-MLYTAB) to overcome these limitations. Our platform employs two key engineered components: a rigid TDN scaffold enables the precise multivalent display of aptamers to enhance binding stability and lysosomal targeting while preventing steric hindrance, and an engineered secondary antibody serves as a universal adaptor, conferring plug-and-play modularity. By simply exchanging the primary antibody, we achieved efficient degradation of multiple distinct cell-surface proteins in different cellular models without platform re-engineering. Compared to conventional flexible and monovalent systems, TDN-MLYTAB uniquely avoids structural collapse, exhibiting substantially improved internalization and a remarkable degradation efficiency of ∼71% at 100 nM after 24 h. This work not only presents a versatile degradation platform but also demonstrates how programmable DNA nanostructures can overcome persistent bioconjugation challenges, advancing modular therapeutics toward application.