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

Area of Science:

• Biomaterials Science
• Nanotechnology
• Gene Therapy

Background:

• Nucleic acid therapeutics require efficient delivery systems to overcome biological barriers.
• Conventional spherical nucleic acids (SNAs) face challenges with endosomal entrapment and degradation.
• Targeting specific cells and avoiding immune system clearance are critical for therapeutic efficacy.

Purpose of the Study:

• To develop an alternative SNA core for improved endosomal escape and therapeutic delivery.
• To investigate pH-sensitive diblock copolymer PMPC25-PDPA72 for self-assembling nucleic acid carriers.
• To evaluate the efficacy of these polymeric SNAs for delivering siRNA against C9orf72 in motor neurons.

Main Methods:

• Self-assembly of PMPC25-PDPA72 diblock copolymers into pH-sensitive polymersomes.
• Conjugation of DNA oligonucleotides to form polymeric SNAs with external and internal coronae.
• Attachment of targeting peptides and siRNA cargo for specific cellular delivery.
• In vitro delivery of siRNA targeting C9orf72 to motor neuron-like cells.

Main Results:

• Polymeric SNAs formed vesicles (polymersomes) with DNA coronae capable of carrying nucleic acid cargoes.
• These polymersomes demonstrated intrinsic endosomal escape via pH-triggered disassembly.
• Targeted delivery of siRNA against C9orf72 to motor neurons achieved effective gene knockdown at low particle doses.

Conclusions:

• pH-sensitive polymeric SNAs offer a promising alternative to nanoparticle-based SNAs for nucleic acid delivery.
• The developed polymersomes overcome endosomal entrapment, enhancing therapeutic potential.
• This platform shows significant promise for targeted gene therapy, exemplified by C9orf72 siRNA delivery for ALS.