Understanding
the synthetic mechanisms and cell–nanoparticle interactions of biosynthesized
and functionalized gold nanoparticles (AuNPs) using natural products
is of great importance for developing their applications in nanomedicine.
In this study, we detailed the biotransformation mechanism of Au(III)
into AuNPs using a hydroxylated tetraterpenoid deinoxanthin (DX) from
the extremophile Deinococcus radiodurans. During the process, Au(III) was rapidly reduced to Au(I) and subsequently
reduced to Au(0) by deprotonation of the hydroxyl head groups of the
tetraterpenoid. The oxidized form, deprotonated 2-ketodeinoxanthin
(DX3), served as a surface-capping agent to stabilize the AuNPs. The
functionalized DX–AuNPs demonstrated stronger inhibitory activity
against cancer cells compared with sodium citrate–AuNPs and
were nontoxic to normal cells. DX–AuNPs accumulated in the
cytoplasm, organelles, and nuclei, and induced reactive oxygen species
generation, DNA damage, and apoptosis within MCF-7 cancer cells. In
the cells treated with DX–AuNPs, 374 genes, including RRAGC
gene, were upregulated; 135 genes, including the genes encoding FOXM1
and NR4A1, were downregulated. These genes are mostly involved in
metabolism, cell growth, DNA damage, oxidative stress, autophagy,
and apoptosis. The anticancer activity of the DX–AuNPs was
attributed to the alteration of gene expression and induction of apoptosis.
Our results provide significant insight into the synthesis mechanism
of AuNPs functionalized with natural tetraterpenoids, which possess
enhanced anticancer potential.