Metal ion-based therapeutic strategies for diabetic wound healing: Mechanisms, biomaterial platforms, and translational challenges.

Abstract

The management of chronic diabetic wounds remains a persistent clinical challenge, characterized by prolonged healing times and high recurrence rates. These wounds typically stall in the inflammatory phase due to multiple overlapping pathological factors, including multidrug-resistant infections, poor microvascular networks, sustained oxidative stress, and impaired immune responses. Traditional single-target treatments struggle to overcome these concurrent barriers; thus, there is a pressing need for multifunctional therapeutic approaches. Metal ions (evolutionarily conserved enzymatic cofactors and redox mediators) provide this mechanistic versatility by coordinating antimicrobial defense, angiogenesis, inflammation resolution, and tissue remodeling through distinct yet complementary pathways. We systematically examine the specific mechanisms of nine functional metal ions (Ag⁺, Cu²⁺, Zn²⁺, Au³⁺, Ce³⁺/Ce⁴⁺, Mg²⁺, Ca²⁺, Mn²⁺, and Co²⁺), and discuss recent advances in bimetallic synergistic platforms (e.g., Fe-Cu, Cu-Ce). To connect biological potential with practical application, we compare diverse delivery architectures (such as stimuli-responsive hydrogels, metal-organic frameworks, electrospun nanofibers, and microneedle patches) focusing on their release kinetics and structural advantages. Finally, we address the primary bottlenecks limiting clinical translation, notably protein corona formation, and outline future directions for designing the next generation of safe, smart, and highly effective metal-based wound dressings.