Nucleoside-stabilized stimuli-responsive lipoic acid supramolecular hydrogel: An efficacious antioxidant and antibacterial platform for chronic diabetic wound repair

Diabetic wound healing remains a critical clinical challenge due to persistent oxidative stress, recurrent infections, and dysregulated inflammation within the wound microenvironment. Consequently, it is desirable to develop advanced dressings capable of microenvironment-adaptive therapy to simultaneously address these pathological conditions. Herein, an innovative guanosine (G₄)-stabilized lipoic acid (LA)-based supramolecular hydrogel integrating LA and G₄ is fabricated through a one-step assembly. This design pioneers a dynamic stabilization strategy wherein the G₄ network's multivalent hydrogen bonds prevent reverse ring-opening depolymerization of polylipoic acid (PolyLA) while enabling on-demand reversible disulfide reconfiguration, thereby overcoming the stability-depolymerization imbalance in conventional LA-based hydrogels. Furthermore, by modulating the content of LA, two types of hydrogels including injectable hydrogels and patch hydrogels are developed tailored for meeting different clinical applications. Both in vitro and in vivo studies demonstrate that these hydrogels exhibit multiple responsiveness, potent reactive oxygen species (ROS) scavenging capacity, significant anti-inflammatory activity, and antibacterial properties, thereby facilitating the healing of diabetic wounds. This innovative approach not only addresses the inherent instability of LA-based hydrogels but also establishes an effective responsive therapeutic platform for chronic wound management. STATEMENT OF SIGNIFICANCE: A newly developed approach addresses the reverse ring-opening depopolymerization of polylipoic acid by employing a guanosine supramolecular network for stabilization. The guanosine network provides robust stabilization while exhibiting multi-stimuli responsiveness, enabling a controllable reverse depolymerization of polylipoic acid that surpasses conventional unidirectional strategies. Importantly, the synthesis conditions for the guanosine network and polylipoic acid are nearly identical, as both require an alkaline pH and elevated temperature. This compatibility allows direct hydrogel formation through a simple process of mixing, heating, and cooling. The resulting hydrogel capitalizes on the inherent biological activities of both lipoic acid and guanosine, demonstrating potent antioxidant and antimicrobial properties alongside multi-stimuli responsiveness for diabetic wound management.