Multidimensional nano-ion composite hydrogel based on enzymatic blood glucose control, gas therapy and ion liquid permeation for repairing diabetic wounds

The multifactorial pathogenesis of diabetic foot ulcers (DFUs) poses significant challenges to effective clinical management. To address this complexity, we have developed a multi-functional ionic composite hydrogel designed to concurrently target four key pathological factors of diabetic wounds. The system integrates: (1) hollow mesoporous silica nanoparticles (HMSNs) encapsulating glucose oxidase (GOx), which protect the enzyme from inactivation in the hyperglycemic and inflammatory wound microenvironment, enabling sustained glucose regulation; (2) L-arginine (LArg), which reacts with the hydrogen peroxide (H 2 O 2 ) byproduct of GOx catalysis to generate nitric oxide (NO), thereby promoting angiogenesis; and (3) an ionic liquid (IL) composed of FeCl 3 and dodecyl dimethyl benzyl ammonium chloride (DDBAC). The [DDBAC] + cation exerts broad-spectrum antibacterial effects via membrane disruption, while the [FeCl 4 ] - anion helps maintain iron homeostasis to support nerve regeneration. Notably, beyond integrating enzymatic glucose control, gas-therapy-mediated angiogenesis, and potent antibacterial action, this work innovatively incorporates a dedicated strategy for peripheral nerve repair. We propose that this combinatorial approach promotes healing by upregulating pro-regenerative pathways (e.g., Angptl4/VEGFA, BDNF/NGFR, FGF2/VEGFA) and inhibiting the deleterious SPINK12/THBS1 axis, offering a transformative multi-target therapeutic platform for DFUs. This study designed a multi-dimensional nanoionic composite hydrogel (Gel-HMSN/GOx-LArg@IL) to address diabetic ulcers through a synergistic approach, including enzymatic glucose regulation, antibacterial activity, nerve repair, and nitric oxide-mediated angiogenesis. The hydrogel integrates hollow silica-protected glucose oxidase, Fe 3+ /DDBAC ionic liquid for antibacterial and neural iron homeostasis, and L-Arginine-derived gas therapy, providing a novel therapeutic approach for treating infected diabetic ulcers.