Dendronized DNA Chimeras Harness Scavenger Receptors To Degrade Cell Membrane Proteins

Abstract Bispecific chimeras bridging cell membrane proteins with lysosome‐trafficking receptors (LTRs) provide an effective therapeutic approach through lysosomal degradation of disease‐relevant targets. Here, we report a novel dendronized DNA chimera (DENTAC) strategy that uses a dendritic DNA to engage cell surface scavenger receptors (SRs) as LTR. Using bioorthogonal strain‐promoted alkyne‐azide cycloaddition to conjugate the dendritic DNA with protein binder, the resulting DENTAC is able to traffic the protein target into the lysosome for elimination. We demonstrated the utility of DENTAC by degrading oncogenic membrane nucleolin (NCL) and epidermal growth factor receptor (EGFR). The anti‐cancer application of NCL‐targeting DENTAC was validated in a mouse xenograft model of lung cancer. This work thus presents a new avenue for rapid development of potent degraders against membrane proteins, with also broad research and therapeutic prospects.