Utilizing RNA nanotechnology to construct negatively charged and ultrasound-responsive nanodroplets for targeted delivery of siRNA.

Abstract

Ultrasound nanodroplets (NDs) have been reported as a promising nanocarrier for siRNA delivery depending on its unique strengths of sonoporation. Presently, common means for NDs-mediated siRNA delivery is through electrostatic interaction, but challenges like cationic toxicity still exist. In this study, we demonstrated a novel strategy to construct negatively charged and ultrasound (US)-responsive O-carboxymethyl chitosan (O-CMS) NDs as a siRNA targeted delivery system through three-way junction of bacteriophage phi29 DNA packaging motor (3WJ-pRNA) nanotechnology. 39nt A10-3.2 aptamer targeting prostate specific membrane antigen (PSMA) and 21nt siRNA against cationic amino acid transporter 1 (siCAT-1) were annealed to 3WJ-pRNA scaffold via complementation with an extended sequence. The cholesterol molecule attached to one branch facilitates the 3WJ-pRNA nanoparticles anchoring onto NDs. The desired O-CMS NDs with siRNA-loading and RNA-aptamer modification (A10-3.2/siCAT-1/3WJ-NDs) were successfully prepared, which were with spherical shapes, core-shell structures and uniform in sizes (198 nm with PDI 0.3). As a main proportion of shell, O-CMC showed a certain anti-tumor effects. In vitro studies demonstrated that A10-3.2/siCAT-1/3WJ-NDs exhibited good contrast-enhanced US imaging, buffering capacity and high bio-safety, were able to deliver siCAT-1 to PSMA-overexpressed prostate cancer cells under US irradiation, thus silence the CAT-1 expression, and consequently suppressing 22RV1 cell proliferation and migration. Taken overall, our findings provide a promising strategy to develop negatively charged and US-responsive NDs for tumor-targeted siRNA delivery.

• Authors: Lu Guo, Dandan Shi, Mengmeng Shang, Xiao Sun, Dong Meng, Xinxin Liu, Xiaoying Zhou, Jie Li
• Journal: Drug delivery (Drug Deliv) Vol. 29 Issue 1 Pg. 316-327 (Dec 2022) ISSN: 1521-0464 [Electronic] England
• PMID: 35037525 (Publication Type: Journal Article)

Chemical References

• Aptamers, Nucleotide
• Cationic Amino Acid Transporter 1
• Drug Carriers
• Nanoparticle Drug Delivery System
• O-carboxymethylchitosan
• RNA, Small Interfering
• Chitosan
• Prostate-Specific Antigen

Topics

• Aptamers, Nucleotide (administration & dosage, pharmacology)
• Bacillus Phages (drug effects)
• Cationic Amino Acid Transporter 1 (administration & dosage, pharmacology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Chemistry, Pharmaceutical
• Chitosan (analogs & derivatives, chemistry)
• Drug Carriers (chemistry)
• Drug Liberation
• Humans
• Nanoparticle Drug Delivery System (chemistry)
• Particle Size
• Prostate-Specific Antigen (drug effects)
• RNA, Small Interfering (administration & dosage, pharmacology)
• Surface Properties
• Ultrasonography, Interventional (methods)