Achievements and challenges in glucose oxidase-instructed multimodal synergistic antibacterial applications

Glucose oxidase (GOx) with unique catalytic properties and inherent biocompatibility can effectively oxidize both endogenous and exogenous glucose with oxygen (O₂) into gluconic acid and hydrogen peroxide (H₂O₂). Accordingly, the GOx-based catalytic chemistry offers new possibilities for designing and constructing multimodal synergistic antibacterial systems. The consumption of glucose permanently downregulates bacterial cell metabolism by blocking essential energy supplies, inhibiting their growth and survival. Additionally, the production of gluconic acid could downregulates the pH within the bacterial infection microenvironment, enhancing the production of hydroxyl radicals (∙OH) from H₂O₂ via enhanced Fenton or Fendon-like reactions and triggering the pH-responsive release of drugs. Furthermore, the generated H₂O₂ in situ avoids the addition of exogenous hydrogen peroxide. Therefore, it is possible to design GOx-based multimodal antibacterial synergistic therapies by combining GOx-instructed cascade reactions with other therapeutic approaches such as chemodynamic therapies (CDT), hypoxia-activated prodrugs, photosensitizers, and stimuli-responsive drug release. Such multimodal strategies are expected to exhibit better therapeutic effects than single therapeutic modes. This tutorial review highlights recent advancements in GOx-instructed multimodal synergistic antibacterial systems, focusing on design philosophy and construction strategies. Current challenges and future prospects for advancing GOx-based multimodal antibacterial synergistic therapies are discussed.