Triggered Antifungal Therapy via <i>Candida</i> ‐Responsive Hydrogels

ABSTRACT Treatment of Candida albicans infections is becoming increasingly challenging due to rising antifungal resistance. Fungi‐responsive drug delivery systems have the potential to effectively treat these infections while reducing toxicity and resistance. Here, a hydrogel platform is developed that is responsive to C. albicans secreted aspartic proteases (Saps) released during different stages of infection. Peptides derived from host antimicrobial peptides, hypothesized to be cleaved by multiple Sap isoenzymes, are incorporated into the poly(ethylene glycol)‐based hydrogels as crosslinkers using thiol‐maleimide chemistry. Only hydrogels containing Saps‐cleavable peptides degrade in the presence of C. albicans . The C. albicans ‐responsive hydrogels exhibit degradation‐dependent release of a model nanoparticle cargo. Incubation in C. albicans Saps knockouts demonstrates an important influence of several Saps in enabling hydrogel degradation, dominated by Sap1‐3. In an ex vivo porcine burn infection model, amphotericin B‐containing liposomes are encapsulated in the hydrogels to assess antifungal efficacy. The responsive hydrogels undergo complete degradation on the infected burn wound in two days, and enable a 7‐log reduction in fungal burden, while non‐responsive hydrogels behave similar to untreated controls. Hydrogel degradation products also maintain fibroblast viability. This C. albicans ‐responsive hydrogel drug delivery system is a promising approach for future treatment of localized C. albicans infections.