Gellan gum and carboxymethyl chitosan-based acid-responsive hydrogels modulate the ROS-macrophage axis to expedite burn wound healing

Severe burn infections and impaired healing remain significant clinical challenges, with high mortality rates linked to immune microenvironment imbalances. While macrophages and reactive oxygen species (ROS) play crucial roles in inflammatory regulation, unilateral ROS modulation proves insufficient for optimal wound repair. This study develops an acid-responsive carboxymethyl chitosan-oxidized gellan gum-gentamicin sulfate (COGS) hydrogel that dynamically regulates the ROS-macrophage axis for enhanced burn treatment. Synthesized through oxidized gellan gum preparation and subsequent cross-linked with carboxymethyl chitosan/gentamicin sulfate via dynamic imine bonds and Ca 2+ -mediated ionic bridges, COGS demonstrates exceptional mechanical strength, self-healing capacity, and acid-responsive antibiotic release. In vitro evaluations reveal superior hemostatic performance and controlled drug release kinetics. In vivo studies demonstrate dual-phase therapeutic action: rapid gentamicin release eliminates pathogens during early infection while elevating ROS to activate M1 macrophages, followed by ROS reduction to promote M2 polarization during tissue regeneration. This dynamic immunomodulation balances inflammatory responses, accelerates tissue repair, and reduces gentamicin-related organ toxicity. By establishing temporal control over ROS levels and macrophage phenotypes, COGS hydrogel contributes to microenvironment remodeling for infectious burn healing. The COGS hydrogel synergistically addresses infection eradication and microenvironment remodeling through dynamic ROS-macrophage crosstalk regulation. This biomaterial-driven strategy advances precision immunotherapy paradigms for severe burn rehabilitation.