Curcumin-Loaded PEGylated Nanoceria Composite Promotes Diabetic Wound Healing by Suppressing Ferroptosis and Modulating the Inflammatory Microenvironment

Diabetic wounds are characterized by persistent oxidative stress, chronic inflammation, and impaired angiogenesis, and current therapies remain inadequate. Herein, we developed a curcumin-loaded PEGylated nanoceria composite (CP@nCeO₂) composed of an ultrasmall nCeO₂ core (5-8 nm) within a PEG/curcumin shell. The nanocomposite exhibited uniform spherical morphology, mixed Ce³⁺/Ce⁴⁺ oxidation states, good colloidal stability, and pH-responsive curcumin release. CP@nCeO₂ retained robust SOD-and CAT-like activities, showed efficient cellular uptake, excellent hemocompatibility, and no significant cytotoxicity at ≤ 75 μg/mL. In HUVECs, CP@nCeO₂ promoted migration, scavenged intracellular and mitochondrial ROS, upregulated VEGF, and suppressed ferroptosis-related markers (GPX4, FSP1, ACSL4) and HMGB1. In STZ-induced diabetic mice, topical CP@nCeO₂ accelerated wound closure, reduced serum CRP and PCT, enhanced re-epithelialization and epidermal thickness, and increased CD31⁺ microvessel density. Mechanistically, CP@nCeO₂ elevated GSH, upregulated GPX4 and FSP1, downregulated ACSL4, and shifted cytokines toward an anti-inflammatory profile (increased IL-4/IL-10; decreased IL-1β, IFN-γ, IL-6). Collectively, CP@nCeO₂ integrates the antioxidant activity of nCeO₂ with the anti-inflammatory and pro-angiogenic effects of curcumin, providing a safe and effective topical nanotherapeutic platform for diabetic wound healing by suppressing ferroptosis, reducing oxidative stress, and modulating inflammation.