A precision nitric oxide-releasing hydrogel promoting nanoparticles permeation for comprehensive nerve-vessel recovery and microenvironment regulation in diabetic wounds

Peripheral neuropathy and microcirculation distribution are key causes of diabetic foot ulcers (DFUs). Based on the vessel dilation and nerve regeneration effect of nitric oxide (NO), a multi-functional nanoparticles-hydrogel therapy system was developed in this research. In order to inhibit the side effect of NO which could form peroxynitrite anions (ONOO^-) and lead to cytotoxicity, dual strategies were purposed, including physiologic NO generation and combination therapy with anti-oxidation. This kind of in situ NO generation was also proved to accelerate the permeation of nanoparticles, mainly by changes of tissue structures or functions. The solid lipid nanoparticles (SLNs) were prepared by microfluidic method, considering the poor stability of both arginine modified cholesterol (Chol-Arg) and reduced coenzyme Q₁₀ that were used in prescription. These Q₁₀/NO-SLNs were then encapsulated in an anti-bacterial and glucose sensitive ε-polylysine (EPL) based hydrogel. The multiple bio-functions of Q₁₀/NO-SLN@EPL^gel system were investigated and proved thoroughly both in vitro and in vivo, including +677.8% wound healing rate, +670.0% nanoparticle permeation, +312.5% blood supply in wound area, and + 229.3% neuron density in wound sections. In conclusion, Q₁₀/NO-SLN@EPL^gel was proved to be an effective DFUs wound dressing, and promoting nerve regeneration should be considered vital in therapy of DFUs.