Oxidized sodium alginate/carboxymethyl chitosan/γ-polyglutamic acid injectable hydrogels enabling pH-responsive synergistic delivery of antimicrobial agents and metal-polyphenol nanoparticles for diabetic foot ulcer healing.

Chronic diabetic wounds have become a major global health challenge due to the vicious cycle driven by infection, oxidative stress, and inflammation. To address this issue, researchers developed a pH-responsive injectable hydrogel (SCP@QCNPs&DOX). The hydrogel is composed of oxidized sodium alginate, dihydrazide-modified γ-polyglutamic acid, and carboxymethyl chitosan, and is co-loaded with quercetin nanoparticles (QCNPs) and doxycycline. The quercetin nanoparticles are prepared via coordination between quercetin and cerium, which not only overcomes the inherent poor water solubility of quercetin but also endows them with antioxidant, anti-inflammatory, and enzyme-mimetic catalytic activities. The SCP@QCNPs&DOX hydrogel exhibits excellent biodegradability, biocompatibility, and stable rheological properties, enabling controlled release of quercetin nanoparticles and doxycycline. The hydrogel alleviates oxidative stress by scavenging reactive oxygen species (ROS) and maintaining mitochondrial membrane potential, inhibits inflammation by modulating the NF-κB pathway and inducing M2 macrophage polarization, and demonstrates potent antibacterial activity against Staphylococcus aureus and methicillin-resistant S. aureus (MRSA). In a diabetic rat model with MRSA infection, the hydrogel significantly suppresses inflammation, exerts antibacterial effects, promotes angiogenesis, and thereby accelerates wound healing. In summary, the SCP@QCNPs&DOX hydrogel represents a promising multifunctional platform for the treatment of infected diabetic wounds.