Immunostimulatory pH-responsive Nanogels Derived from Poly(oxanorbornene) Precursor Polymers

Ring Opening Metathesis Polymerization (ROMP) provides access to well-defined poly(oxanorbornene) block copolymers that can be converted into micellar-derived immunoactive nanogels. We report on the synthesis of such immunoactive nanogels based on oxanorbornene-derived post-polymerization modification strategy. The key precursor, an oxanorbornene pentafluorophenyl ester (ONB-PFP) monomer, was synthesized and polymerized using living ring-opening metathesis polymerization (ROMP) facilitated by a third-generation Grubbs catalyst (G3) for efficient living-type block copolymerization. This approach yielded well-defined block copolymers by incorporating an active ester monomer with a hydrophilic triethylene glycol-functionalized oxanorbornene, establishing a robust platform for subsequent post-polymerization modifications. Nanogels were formed by aqueous self-assembly of the block copolymers, with various crosslinking agents employed to generate both acid-labile (D-NG) and non-degradable (ND-NG) nanogels, while without crosslinkers fully hydrophilic single polymer chains were obtained as controls. The covalent attachment of the Toll-like receptor 7/8 agonist IMDQ, an immunomodulatory imidazoquinoline agent, to the nanogels produced immunoactive nanogels, whose immunostimulatory efficacy was evaluated in vitro using a RAW-Blue macrophage reporter cell line. Flow cytometry confirmed efficient cellular uptake of only the intact nanogels by the macrophages resulting in a receptor activation and thus providing a strategy to safely control the delivery of the highly potent TLR7/8 agonist.