Bio-inspired supramolecular hydrogel inhibits ferroptosis to accelerate diabetic wound healing

Ferroptosis significantly compromises diabetic wound healing and represents a promising therapeutic target for clinical intervention. Baicalein (Bai), a natural flavonoid, has been considered to own ferroptosis-regulating properties, while the underlying mechanisms remain understood.

The study aims to investigate potential mechanisms by which Bai inhibits ferroptosis in endothelial cells and validate the therapeutic efficacy of Bai-loaded hydrogel on diabetic wounds.

High-glucose-cultured human umbilical vein endothelial cells (HUVECs) were chosen to study Bai's molecular mechanisms inhibiting ferroptosis. Subsequently, a Bai@GA/Gel/Zn²⁺ supramolecular nanofibrous hydrogel was developed for active Bai delivery. Its wound-healing efficacy and underlying mechanisms were further evaluated in a diabetic rat model.

In vitro experiments, HUVECs were observed to exhibit characteristic ferroptosis, which were induced by high-glucose (HG) microenvironment, leading to compromised cellular functions. Through the inhibition of ferroptosis in HUVECs, Bai effectively promoted cell growth, migration, and angiogenesis. Herein, we further reveal that Bai inhibits HG-induced ferroptosis by modulating the Keap1/NRF2/HIF-1α signaling axis. To optimize therapeutic delivery, Bai was encapsulated into supramolecular nanofibers self-assembled from glycyrrhizic acid (GA), followed by cross-linking with gelatin (Gel) and zinc ions (Zn²⁺) to form a hydrogel (Bai@GA/Gel/Zn²⁺), thereby enabling sustained release of Bai at the wound-healing interface. Bai@GA/Gel/Zn²⁺ nanofiber-incorporated hydrogel demonstrated favorable mechanical and biological properties, markedly reducing ferroptosis levels and accelerating diabetic wound healing.

In summary, our findings reveal the ferroptosis-inhibiting mechanism of Bai and develop a Bai@GA/Gel/Zn²⁺ supramolecular nanofibrous hydrogel that synergistically enhances diabetic wound healing with proven therapeutic efficacy.