Anti-Candida Activity of Cysteine-Modified Amidated Decoralin in the Presence of Engineered Nanomaterials

<b>Background:</b> Candidiasis remains a chief concern in global healthcare. Drug safety issues and increasing resistance make it urgent to develop alternative antifungal agents, namely antimicrobial peptides. Amidated decoralin (Dec-CONH₂) possesses considerable anti-<i>Candida</i> activity, and its association with nanocarriers could help in enhancing efficacy while reducing intrinsic toxicity to the host. <b>Methods:</b> We studied an <i>N</i>-terminal cysteine-modified version of the peptide (Cys-Dec-CONH₂) and screened the effects of different nanosystems (polymeric nanoparticles (NPs), liposomes and gold NPs) on its activity against azole-sensitive and azole-resistant <i>Candida</i> species using a clinically relevant in vitro assay. <b>Results:</b> The antifungal activity of Cys-Dec-CONH₂ was maintained (minimum inhibitory concentration (MIC) = 16-64 µg/mL), but the presence of poly(d,l-lactic-co-glycolic acid) (PLGA)- and polycaprolactone-based NPs impaired the antifungal effect of the peptide (MIC > 256 µg/mL). This effect was milder for polystyrene-based NPs, liposomes, and gold NPs (MIC ≤ 128 µg/mL). Additionally, the covalent surface functionalization of PLGA-based NPs with Cys-Dec-CONH₂ or the presence of relevant biomolecules (albumin and mucin) resulted in complete inhibition of antifungal activity. <b>Conclusions:</b> Our data suggest that Cys-Dec-CONH₂ is able to establish strong interfacial interactions with different nanomaterials, which need to be considered when developing nanomedicines based on this peptide for the management of candidiasis.