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Host defense peptides (HDPs) are encouraged as anticancer and antimicrobial agents. Thus, this study aimed to investigate the effect of oleic acid (OA)- and linoleic acid (LA)-loaded nanosomes on the gene expression of beta-defensin-4 (BD-4) as a member of HDPs. The OA and LA nanosomes were prepared and characterized in terms of particle size and surface charge as lymphatic delivery systems. Afterwards, the effect of fatty acid (FA)-loaded nanosomes on BD-4 gene expression in mice dermal cells was investigated using polymerase chain reaction at 6, 12, and 24 h intervals. The epigenetic effect of OA and LA on histone deacetylase-6 (HDAC6) was studied using the molecular operating environment (MOE) docking. Moreover, the cytotoxic effect of free and FA-loaded nanosomes was investigated using 375 cell lines. The present results indicated that the prepared OA and LA nanosomes have a nanosize range (258–275 nm), negative zeta potential (−26 to −32 mV), and are homogenous polydispersity index (0.200–0.400). Moreover, free, and FA-loaded nanosomes induced significant upregulation of BD-4 mRNA expression after 6 and 12 h compared to the control mice BD-4 gene expression by several folds. However, after 24 h, the BD-4 mRNA expression significantly decreased compared to 12 h. Molecular docking studies revealed that OA and LA inhibit HDAC6 by binding with the active site. Treating the melanoma cell line with free or OL- and LA-loaded nanosomes induced significant cell death compared to negative control. This study suggests new insight into the effect of OA and LA on HDPs production. Consequently, the consumption of oils enriched with OL and LA stimulates the host immune system to fight microbial invasion and cancer. Moreover, Nanosomes are suggested as influential tactics for the specific lymphatic delivery of cytotoxic medicines.

Oleic acid and linoleic acid nanosomes boost immunity and provoke cell death via the upregulation of beta-defensin-4 at genetic and epigenetic levels