Aptamer as a Molecular Tethering Agent Induces PrP ^C Aggregation and Degradation to Inhibit Melanoma Proliferation

Melanoma, a malignant tumor originating from melanocytes, is the most aggressive and deadly form of skin cancer. Previous studies have revealed that the cellular prion protein (PrP^C) is frequently overexpressed in melanoma, contributing to tumor progression. This study presents the first proof of concept evidence that nucleic acid aptamers can be used to construct a molecular tethering agent that regulates PrP^C protein levels by inducing membrane-bound PrP^C aggregation for antimelanoma therapy. Using a screening strategy combining cell-SELEX and cell-internalization SELEX, we obtained ssDNA aptamer, TT-1e, specifically binding to melanoma cells and tissues. We identified that the binding site of TT-1e is located at the octapeptide repeat region of glycosylated PrP^C. Based on the binding characteristics of TT-1e, we engineered an aptamer-based molecular tethering agent TTe-TTe. We found that TTe-TTe induces aggregation of cell surface PrP^C, promoting its internalization and facilitating its lysosomal degradation. This process resulted in the inhibition of AKT pathway activation. Importantly, in vivo studies confirmed the ability of TTe-TTe to target melanoma xenografts and suppress tumor growth through this unique mechanism. Our study presents a promising strategy for targeted melanoma therapy and introduces a paradigm-shifting approach for manipulating protein levels using aptamers as molecular tethering agents.