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

Xiaoxing Chen1,2, Qianqian Gao3, Linlin Yang4

  • 1Institute of Molecular Medicine, Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 200127 Shanghai, China.

Nano Letters
|March 17, 2026
PubMed

Insights

This study introduces a novel dual-action therapeutic molecule combining targeted protein degradation and RNA interference to combat cancer. This innovative approach effectively degrades cancer-driving proteins and silences their genes, showing significant antitumor effects.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Tumor progression is complex, often involving undruggable protein targets.
  • Targeted protein degradation (TPD) and RNA interference (RNAi) offer complementary strategies for disease-driving protein elimination.
  • Integrating TPD and RNAi into a single molecule presents a significant therapeutic challenge.

Purpose of the Study:

  • To develop a novel single-molecule therapeutic platform integrating TPD and RNAi.
  • To demonstrate the efficacy of this dual-mechanism approach against cancer targets.
  • To establish a versatile platform for precision oncology therapeutics.

Main Methods:

  • Design and synthesis of a Dicer-activatable aptamer-adamantane/siRNA (AptHyT-siRNA) chimera.
  • Demonstration of chimera cleavage within cells, releasing functional AptHyT degrader and siRNA.
  • Utilizing the androgen receptor (AR) in castration-resistant prostate cancer (CRPC) as a proof-of-concept target.

Main Results:

  • The AptHyT-siRNA chimera successfully achieved synergistic AR degradation and mRNA knockdown.
  • Demonstrated robust antiproliferative and antitumor activities in vitro and in vivo.
  • Validated the dual-mechanism therapeutic strategy for cancer treatment.

Conclusions:

  • A novel AptHyT-siRNA chimera platform enables simultaneous protein degradation and gene silencing.
  • This dual-mechanism oligonucleotide therapeutic shows significant potential for treating castration-resistant prostate cancer.
  • The platform offers a versatile approach for broad applications in precision oncology.
Keywords:
AptamerHydrophobic TagsProtein degradationsiRNA

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