A modular RNA delivery system comprising spherical nucleic acids built on endosome-escaping polymeric nanoparticles

• Published in: Nanoscale advances 2023-05, Vol.5 (11), p.2941-2949
• Main Authors: Garcia-Guerra, Antonio, Ellerington, Ruth, Gaitzsch, Jens, Bath, Jonathan, Kye, Mahnseok, Varela, Miguel A, Battaglia, Giuseppe, Wood, Matthew J. A, Manzano, Raquel, Rinaldi, Carlo, Turberfield, Andrew J
• Format: Article
• Language: English
• Subjects: Chemistry
• ISSN: 2516-0230; 2516-0230
• DOI: 10.1039/d2na00846g

Nucleic acid therapeutics require delivery systems to reach their targets. Key challenges to be overcome include avoidance of accumulation in cells of the mononuclear phagocyte system and escape from the endosomal pathway. Spherical nucleic acids (SNAs), in which a gold nanoparticle supports a corona of oligonucleotides, are promising carriers for nucleic acids with valuable properties including nuclease resistance, sequence-specific loading and control of receptor-mediated endocytosis. However, SNAs accumulate in the endosomal pathway and are thus vulnerable to lysosomal degradation or recycling exocytosis. Here, an alternative SNA core based on diblock copolymer PMPC 25 -PDPA 72 is investigated. This pH-sensitive polymer self-assembles into vesicles with an intrinsic ability to escape endosomes via osmotic shock triggered by acidification-induced disassembly. DNA oligos conjugated to PMPC 25 -PDPA 72 molecules form vesicles, or polymersomes, with DNA coronae on luminal and external surfaces. Nucleic acid cargoes or nucleic acid-tagged targeting moieties can be attached by hybridization to the coronal DNA. These polymeric SNAs are used to deliver siRNA duplexes against C9orf72 , a genetic target with therapeutic potential for amyotrophic lateral sclerosis, to motor neuron-like cells. By attaching a neuron-specific targeting peptide to the PSNA corona, effective knock-down is achieved at doses of 2 particles per cell. Polymeric spherical nucleic acids comprise pH-sensitive, polymer-conjugated oligonucleotides that self-assemble into nanoparticles with the ability to escape endosomes, overcoming a major obstacle in nucleic acid delivery.