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The functional activities of gold nanoparticles (AuNPs) on biological systems depend on their physical-chemical properties and their surface functionalizations. Within a biological environment and depending on their surface characteristics, NPs can adsorb biomolecules (mostly proteins) present in the microenvironment, thereby forming a dynamic biomolecular corona on the surface. The presence of this biocorona changes the physical-chemical and functional properties of the NPs and how it interacts with cells. Here, we show that primary human epidermal keratinocytes (HEK) exposed in culture to branched polyethyleneimine (BPEI)-AuNPs, but not to lipoic acid (LA)-AuNPs, show potent particle uptake, decreased cell viability and enhanced production of inflammatory factors, while the presence of a human plasma-derived biocorona decreased NPs uptake and rescued cells from BPEI-AuNP-induced cell death. The mechanistic study revealed that the intracellular oxidative level greatly increased after the BPEI-AuNPs treatment, and the transcriptomic analysis showed that the dominant modulated pathways were related to oxidative stress and an antioxidant response. The stress level measured by flow cytometry also showed a significant decrease in the presence of a biocorona. Further anaylsis discovered that nuclear factor erythroid-2 related factor (Nrf2), a major regulator of anti-oxidant and anti-inflammatory genes, as the key factor related to the AuNPs induced oxidative stress and inflammation. This study provides futher understanding into the mechanisms on how NPs-induced cellular stress and reveals the protective effects of a biocorona on inflammatory responses in HEK at the molecular level, which provides important insights into the biological responses of AuNPs and their biocorona. [Display omitted] • BPEI- but not LA-AuNPs caused potent particle uptake, induced cytotoxicity, enhanced inflammation in human keratinocytes. • Intracellular ROS that induced by BPEI-AuNPs was the mainly reason for these adverse effects. • Nrf2 was the key mediator related to the BPEI-AuNPs induced oxidative stress and inflammation. • The presence of biocorona suppressed the adverse effects caused by BPEI-AuNPs in keratinocytes in vitro. [ABSTRACT FROM AUTHOR]