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  2. Conjugated Polyelectrolyte/Single Strand DNA Hybrid Polyplexes for Efficient Nucleic Acid Delivery and Targeted Protein Degradation

Conjugated Polyelectrolyte/Single Strand DNA Hybrid Polyplexes for Efficient Nucleic Acid Delivery and Targeted Protein Degradation

  • ACS Appl Mater Interfaces. 2023 Dec 18. doi: 10.1021/acsami.3c14640.
Yuanjie Sun 1 Li Jiang 2 Zhilin Zhang 1 Naihan Xu 1 3 Yuyang Jiang 1 Chunyan Tan 1 4
Affiliations

Affiliations

  • 1 The State Key Laboratory of Chemical Oncogenomics, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, People's Republic of China.
  • 2 State Assets Management Office, Shenzhen Polytechnic University, Shenzhen 518055, People's Republic of China.
  • 3 School of Food and Drug, Shenzhen Polytechnic University, Shenzhen 518055, People's Republic of China.
  • 4 Open FIESTA, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, People's Republic of China.
Abstract

Nucleic acid-based therapeutics have gained increasing attention due to their ability to regulate various genetic disorders. However, the safe and effective delivery of nucleic acids to their intended cellular sites remains a challenge, primarily due to poor cell membrane permeation and low in vivo stability. Limitations associated with the commonly used nucleic acid delivering agent viral vectors such as carcinogenesis and immunogenicity have driven scientists to develop various nonviral vectors. In this study, we present a highly efficient nucleic acid delivery system based on cationic conjugated polyelectrolytes and single-strand DNA polyplexes with further application in efficient ubiquitin-regulated targeting protein degradation. These polyplexes, formed by 9TC, an aptamer sequence for Estrogen Receptor (ERα), and cationic PPET3N2 through electrostatic and hydrophobic interactions, demonstrate improved cellular uptake efficiency as well as enhanced stability against nuclease degradation. Furthermore, by incorporation of 9TC into a proteolysis targeting chimera (PROTAC) molecule (P9TC), PPET3N2/P9TC polyplexes significantly enhance the target protein ERα degradation efficiency. Collectively, our findings suggest that PPET3N2 provides a versatile, low cytotoxicity platform for safe, efficient, and simplified delivery of nucleic acids.

Keywords

PROTACs; aptamers; conjugated polyelectrolytes; nucleic acid delivery; polyplexes; targeted protein degradation.

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