Assembled Hyaluronic Acid Therapeutics for Targeting M1 Macrophages and Regulating Immune Homeostasis for Ulcerative Colitis Treatment.

Hyperactivated M1 macrophages with excessive reactive oxygen species (ROS) exacerbate intestinal inflammation, driving the progression of inflammatory bowel diseases (IBDs), for instance, ulcerative colitis. Current standard treatments for IBDs show limited efficacy and off-target side effects. Herein, we develop an oral, drug-free hyaluronic acid (HA)-based therapeutics that could self-assemble in aqueous solution, accumulate in inflamed colons and attenuate M1-like activation, thereby rebalancing the colonic immune landscape. Such drug-free therapeutics are generated by the conjugation of unsaturated fatty acids to HA via dynamic covalent boronate-catechol ester bonds. Mechanistically, the nano-assemblies (termed uhNAs) effectively scavenge ROS, dampen NF-κB signaling, and diminish pro-inflammatory cytokines in M1-like phenotypes. In DSS-induced acute colitis, oral uhNAs treatment elicits significant decreases in M1-like macrophages, CD8+ T cells, and neutrophils with concomitant increases in Tregs. In chronic and relapsing DSS colitis, uhNAs also confer robust protection, supporting sustained colonic immune remodeling during recurrent intestinal inflammation. Single-cell RNA-sequencing corroborates these shifts and maps the myeloid, B and T-cell programs, highlighting the downregulated inflammatory responses following uhNAs treatment. Notably, uhNAs-OA outperform physical HA (or HA-PBA)/oleic-acid mixtures, and two clinically established IBD drugs (5-aminosalicylic acid and dexamethasone), protecting mice models against both acute and chronic colitis.