A Dicer-Activatable Aptamer-Adamantane/siRNA (AptHyT-siRNA) Chimera Enables Synergistic Targeted Protein Degradation and mRNA Silencing.

Tumor progression remains a significant challenge due to the complexity of oncogenesis and the prevalence of undruggable protein targets. Strategies such as targeted protein degradation (TPD) and RNA interference (RNAi) have emerged as complementary approaches to eliminate disease-driving proteins at the protein and transcript levels, respectively. However, the integration of these mechanisms within a single-molecule construct has not been realized. Here, we report a Dicer-activatable aptamer-adamantane/siRNA (AptHyT-siRNA) chimera that combines hydrophobic tagging-induced proteasomal degradation with siRNA-mediated gene silencing. Upon cleavage inside cells, the chimera releases both a functional AptHyT degrader and a siRNA duplex. As a proof of concept, we chose the androgen receptor (AR) in castration-resistant prostate cancer (CRPC) as a target to demonstrate synergistic AR degradation and mRNA knockdown. This resulted in robust antiproliferative and antitumor activities in vitro and in vivo. Our findings establish a versatile platform for dual-mechanism oligonucleotide therapeutics with potential for broad application in precision oncology.