Craig L. Duvall

Nanoparticle (NP) supra‐assembly offers unique opportunities to tune macroscopic hydrogels’ mechanical strength, material degradation, and drug delivery properties. Here, synthetic, reactive oxygen species (ROS)‐responsive NPs are physically cross‐linked with hyaluronic acid (HA) through guest‐host chemistry to create shear‐thinning NP/HA hydrogels. A library of triblock copolymers composed of poly(propylene sulfide)‐ b ‐poly(N, N ‐dimethylacrylamide)‐ b ‐poly(N, N ‐dimethylacrylamide‐ co ‐N‐(1‐adamantyl)acrylamide) are synthesized with varied triblock architectures and adamantane grafting densities and then self‐assembled into NPs displaying adamantane on their surface. Self‐assembled NPs are mixed with β‐cyclodextrin grafted HA to yield eighteen NP/HA hydrogel formulations. The NP/HA hydrogel platform demonstrates superior mechanical strength to HA‐only hydrogels, susceptibility to oxidative/enzymatic degradation, and inherent cell‐protective, antioxidant function. The performance of NP/HA hydrogels is shown to be affected by triblock architecture, guest/host grafting densities, and HA composition. In particular, the length of the hydrophilic second block and adamantane grafting density of self‐assembled NPs significantly impacts hydrogel mechanical properties and shear‐thinning behavior, while ROS‐reactivity of poly(propylene sulfide) protects cells from cytotoxic ROS and reduces oxidative degradation of HA compared to HA‐only hydrogels. This study provides insight into polymer structure‐function considerations for designing hybrid NP/HA hydrogels and identifies antioxidant, shear‐thinning hydrogels as promising injectable delivery platforms for small molecule drugs and therapeutic cells.