Introducing Degradable Cationic Nanogels Carrying TLR9 Stimulating Oligonucleotides

Abstract Cationic, core‐crosslinked nanogel particles are prepared from synthetic biodegradable materials. These fully hydrophilic nanogels offer superior customizability compared to common lipid nanoparticles, thereby circumventing intrinsic immune stimulatory properties. Electrostatic loading allows for complexation of nucleic acids including the immune stimulatory Toll‐like receptor 9 (TLR9) agonistCpG‐ODN (cytidine‐phosphate‐guanosine oligodeoxynucleotide). Only when complexed inside nanogels, one can control CpG‐ODN's biodistribution, prevent systemic toxicity, and increase bioavailability at target locations. Nanogels are prepared from cyclic aliphatic carbonate monomers with reactive pentafluorophenyl (PFP) esters. First, block copolymers are acquired via cationic ring opening polymerization (CROP) onto polyethylene glycol (PEG). Upon self‐assembly in ethanol, the micelles’ core is cationically core‐crosslinked, and the resulting fully hydrophilic particles exhibit sizes of ≈20 nm, also upon loading with CpG‐ODN. In vitro, they promote intracellular delivery devoid of carrier‐related toxicities, while retaining the immune stimulatory properties of the TLR agonist cargo. In vivo, the nanogels reduce systemic liver immune responses and remain near the injection site. Additionally, delivery into cDC1 (conventional dentritic cells type 1) antigen‐presenting cells, which are highly relevant for antitumoral T‐cell immune responses, is confirmed. Altogether, cationic, core‐crosslinked polycarbonate nanogels show promise for nucleic acid delivery, showcasing controlled immunostimulatory cargo delivery and an enhanced hydrolytic biodegradability profile, highly valuable for cancer immunotherapy.