Multifunctional hyaluronic acid-decorated polyamidoamine dendrimers enhance drug solubility and enable precision therapy for ulcerative colitis.

The therapeutic management of inflammatory bowel disease (IBD) remains challenging by poor drug bioavailability, limited mucosal targeting, and chronic immune dysregulation. In this study, we report the synthesis and characterization of hyaluronic acid (HA)-decorated polyamidoamine (PAMAM) dendrimers as a multifunctional nanoplatform for targeted delivery of 5-aminosalicylic acid (5ASA), with concurrent antioxidant and immunomodulatory benefits. PAMAM dendrimers (G1.0-G4.0) were synthesized via the Tomalia method and conjugated to HA. Characterization by dynamic light scattering, zeta potential, and electron microscopy showed nanoscale size, stability, and successful functionalization. HA decoration enhanced biocompatibility, reduced hemolysis, and promoted CD44-mediated uptake in macrophages and colonic epithelial cells. The conjugates displayed strong ROS scavenging and polarized macrophages toward an anti-inflammatory M2 phenotype. HA-modified dendrimers improved 5ASA solubility and colonic accumulation, confirmed by FITC biodistribution. In vivo, the PAMAM G4-HA+5ASA complex outperformed free 5ASA in TNBS-induced colitis, reducing inflammation, promoting mucosal repair, and showing favorable pharmacokinetics. While unmodified dendrimers had slightly higher drug loading, HA conjugates offered superior targeting, immune modulation, and safety without systemic toxicity. These results highlight HA-decorated PAMAM dendrimers as promising carriers for site-specific drug delivery and immunotherapy in chronic inflammation.