SETDB1 and neoplasm: Here, we report the development and characterization of dual aptamer-based PROTACs targeting SET domain bifurcated histone lysine methyltransferase 1 (SETDB1), a key epigenetic regulator implicated in breast cancer progression, drug resistance, and tumor immune evasion. Using the Systematic Evolution of Ligands by Exponential Enrichment (SELEX) process, we identified a high-affinity single-stranded DNA (ssDNA) aptamer against SETDB1.