Antimicrobial Nanoparticles Composed of Zein and Arginine-Phenylalanine-Based Surfactants for Wound Related Infections: Antioxidant and Skin-Related Anti-Enzymatic Activities and Toxicity

<b>Background/Objectives</b>: Cationic surfactants are potential antimicrobial candidates. Even so, they are the foremost irritative and incompatible group, which limits their usage. The incorporation of surfactants in biopolymer-based nanoparticles is a feasible strategy to improve their efficacy and reduce those drawbacks. <b>Methods</b>: Surfactants with one amino acid on the polar head (lauroyl arginine methyl ester-LAM and phenylalanine dodecyl amide-PNHC₁₂) and surfactants with two amino acids on the polar heads, arginine-phenylalanine (Lauroyl phenylalanine arginine methyl esther-C₁₂PAM and phenylalanine-arginine dodecyl amide-PANHC₁₂) were loaded to zein nanoparticles. Their antimicrobial and antibiofilm activities were evaluated. Also, the inhibitory activities of the surfactants and nanoparticles over skin-related enzymes were accessed in silico and in vitro, while their cytotoxicity was determined comparatively over immortal human keratinocytes (HaCaT) and human fibroblasts (3T3). Finally, the <i>Vibrio fisheri</i> luminescence reduction test was used to detect its ecotoxicity. <b>Results</b>: The nanoparticles were obtained successfully and exhibited good biocide activity against a wide range of pathogenic bacteria and yeasts. The surfactants were found active over the enzymes assayed: elastase > tyrosinase > collagenase > lipoxygenase, while the inhibitory activity was superior when nanoencapsulated over the enzymes tyrosinase and lipoxygenase. The surfactants and their corresponding nanoparticles presented acceptable cytotoxic levels, except for PNHC₁₂ in both forms, while their ecotoxicity was limited and acceptable. <b>Conclusions</b>: Accordingly, the nanoencapsulation of the arginine-phenylalanine surfactants loaded to zein nanoparticles was found to be a smart strategy to enhance the antimicrobial activity and improve their selectivity over representative skin and connective tissues cell lines. These biological properties render the arginine-phenylalanine surfactant nanoparticles as promising candidates for antimicrobial and tissue repairing applications in wound treatments.