Introducing Degradable Cationic Nanogels Carrying TLR9 Stimulating Oligonucleotides

Area of Science:

• Biomaterials Science
• Nanotechnology
• Immunology

Background:

• Lipid nanoparticles face limitations in customizability and can trigger immune responses.
• Nucleic acid delivery requires precise control over biodistribution and toxicity.
• Toll-like receptor 9 (TLR9) agonists, like CpG-ODN, show therapeutic potential but require safe delivery systems.

Purpose of the Study:

• To develop novel, fully hydrophilic, cationic nanogels for enhanced nucleic acid delivery.
• To investigate the customizability and immune-modulating capabilities of these nanogels.
• To evaluate the safety, efficacy, and biodistribution of nanogel-delivered CpG-ODN in vitro and in vivo.

Main Methods:

• Preparation of cationic, core-crosslinked nanogels from biodegradable cyclic aliphatic carbonate monomers.
• Electrostatic complexation of nucleic acids, including the TLR9 agonist CpG-ODN.
• Characterization of nanogel size, properties, and cargo loading.
• In vitro assessment of intracellular delivery and immune stimulation.
• In vivo evaluation of biodistribution, systemic toxicity, and immune responses.

Main Results:

• Successfully synthesized ≈20 nm fully hydrophilic nanogels with tunable properties.
• Demonstrated efficient intracellular delivery of CpG-ODN without carrier toxicity in vitro.
• Confirmed retention of TLR9 agonist immune stimulatory properties upon complexation.
• Observed reduced systemic liver immune responses and localized delivery in vivo.
• Showed targeted delivery to conventional dendritic cells type 1 (cDC1) in vivo.

Conclusions:

• Cationic, core-crosslinked nanogels provide a versatile platform for nucleic acid delivery.
• These nanogels enable controlled delivery of immunostimulatory cargo, mitigating systemic toxicity.
• The enhanced biodegradability and targeted delivery profile make them promising for cancer immunotherapy applications.