Securing LYTAC with Logic‐Identification System for Cancer Cell‐Selective Membrane Protein Degradation

Abstract Lysosome‐targeting chimera (LYTAC) links proteins of interest (POIs) with lysosome‐targeting receptors (LTRs) to achieve membrane protein degradation, which is becoming a promising therapeutic modality. However, cancer cell‐selective membrane protein degradation remains a big challenge considering expressions of POIs in both cancer cells and normal cells, as well as broad tissue distribution of LTRs. Here a logic‐identification system is designed, termed Logic‐TAC, based on cell membrane‐guided DNA calculations to secure LYTAC selectively for cancer cells. Logic‐TAC is designed as a duplex DNA structure, with both POI and LTR recognition regions sealed to avoid systematic toxicity during administration. MCF‐7 and MCF‐10A are chosen as sample cancer cell and normal cell respectively. As input 1 for logic‐identification, membrane proteins EpCAM, which is highly expressed by MCF‐7 but barely by MCF‐10A, reacts with Logic‐TAC to expose POI recognition region. As input 2 for logic‐identification, Logic‐TAC binds to POI, membrane protein MUC1, to expose LTR recognition region. As output, MUC1 is connected to LTR and degraded via lysosome pathway selectively for cancer cell MCF‐7 with little side effect on normal cell MCF‐10A. The logic‐identification system also demonstrated satisfactory in vivo therapeutic results, indicating its promising potential in precise targeted therapy.