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

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.