Amyloid-Reinforced Hyaluronic Acid Composite Hydrogel Enabling Controlled Curcumin Delivery, Antibiofilm Photothermal Therapy, and Accelerated Diabetic Wound Healing.

Abstract

Chronic diabetic wounds are characterized by persistent oxidative stress, impaired angiogenesis, and biofilm-associated infections, necessitating multifunctional biomaterials capable of modulating the wound microenvironment. Herein, we report an amyloid-reinforced hyaluronic acid (HA) composite hydrogel that integrates mechanical robustness, controlled drug delivery, and bioactive functionality within a single platform. The hydrogel is constructed through interpenetrating protein-polysaccharide networks, where thermally induced bovine serum albumin amyloid fibrils act as reinforcing scaffolds within the HA matrix via hydrogen bonding and chain entanglement. This architecture enhances viscoelastic properties, swelling behavior, and structural stability compared to nonreinforced systems. Curcumin is incorporated as a multifunctional therapeutic agent, exhibiting sustained and pH-responsive release governed by hydrophobic and π-π interactions within the composite network. The hydrogel demonstrates pronounced antibacterial and antibiofilm activity against both Gram-positive and Gram-negative bacteria, which is further amplified under near-infrared (NIR) irradiation via photothermal effects. In vitro studies confirm excellent cytocompatibility, hemocompatibility, and enhanced fibroblast migration, indicating favorable cellular interactions. Importantly, in a streptozotocin-induced diabetic wound model, the composite hydrogel significantly accelerates wound closure, promotes collagen deposition and neovascularization, and restores oxidative stress biomarkers toward physiological levels. Mechanistically, the combined integration of amyloid-mediated mechanical reinforcement, HA-driven bioactivity, and curcumin-enabled therapeutic functionality enables the simultaneous regulation of infection, inflammation, and tissue regeneration. This study establishes a protein-polysaccharide hybrid hydrogel platform that couples structural reinforcement with stimuli-responsive therapeutic delivery, offering a promising strategy for advanced diabetic wound management and translational biomaterial design.