Substrate Induced Regulation of Rigidity of G4‐Hydrogels: Toward Peroxidase‐Mimic Facilitated Eradication of Fungi via Turning a Metabolic Friend to a Foe

ABSTRACT The necessity of eliminating fungal infections is vital, given their significant mortality rates, particularly among immunocompromised individuals. Proper care and control of Candida ‐related infections are essential to prevent the emergence and spread of drug‐resistant strains, emphasizing the urgency of developing effective antifungal strategies. The ability of Candida to generate biofilms shields fungal cells from antifungal drugs, emphasizing the need for innovative therapeutic approaches. This study explores the synthesis of G4‐hydrogels through self‐assembly of guanosine nucleoside. The hydrogels are thermo‐reversible and demonstrate substrate‐induced modulation of mechanical properties, with the 2G hydrogel displaying superior performance. Circular dichroism experiments reveal the chirality of the molecular organization, correlating with gel stiffness. Furthermore, we report a hydrogel system having peroxidase mimicking activity via utilizing glucose oxidase and hemin. This system exhibits antifungal activity against Candida albicans and Candida tropicalis in both planktonic and biofilm states. The current strategy has shown a reduction in fungal growth of 84% in planktonic state an d ≈4‐fold reduction in biofilm thickness as supported by in vitro experiments. In vivo studies on aneutrophilic mice validate the efficacy of the hydrogel system in inhibiting fungal growth and biofilm formation, highlighting its potential as a therapeutic strategy against pathogenic fungal pathogen C albicans .