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This study demonstrates a facile strategy by using chemically-synthesized lentinan-functionalized selenium nanoparticles (LNT-SeNPs) that could be simply obtained in large scale and display high antioxidative and anti-inflammatory activities to treat postoperative cognition dysfunction (POCD), and suggests that the use of translational LNT-SeNPs could be further developed as potent strategy for prevention and therapy of surgery-induced cognitive impairment. [Display omitted] • Our chemically-synthesized LNT-SeNPs that could be simply obtained in large scale. • LNT-SeNPs increased detoxifying selenoproteins in both serum and hippocampus. • LNT-SeNPs supplements significantly improved surgery-induced cognitive dysfunction. • LNT-SeNPs alleviated surgery-induced oxidative stress and neuroinflammation. • LNT-SeNPs also improved gut microbiome and intestinal barrier function. Postoperative cognition dysfunction (POCD) describes a condition of persistent deficits in attention, learning and memory following surgery. The mechanisms of POCD are far from being understood and the therapeutic strategies are limit. Surgery-induced oxidative stress and peripheral inflammation form a feedforward loop and eventually resulted in neuroinflammation, which underpin the pathogenesis of POCD. Therefore, the reactive oxygen species (ROS) homeostasis are tightly regulated by detoxifying enzymes, most of which are recognized as selenoproteins. The putative neuroprotective function of this trace element was investigated in this study using aged mice with POCD. Herein we demonstrate a facile strategy by using chemically-synthesized lentinan-functionalized selenium nanoparticles (LNT-SeNPs) that could be simply obtained in large scale and display high antioxidative and anti-inflammatory activities, to treat POCD. As expected, we found that, dietary supplements of LNT-SeNPs were effectively ingested and increased the levels of detoxifying selenoproteins in both serum and hippocampus of our aged mice. Behavioral assessments showed that LNT-SeNPs significantly improved the surgery-induced cognitive dysfunction, by alleviating surgery-induced oxidative stress and pro-inflammatory cytokine expression. In addition, dietary supplementation of LNT-SeNPs might protect central nervous system (CNS) function by improving gut microbiome and intestinal barrier function. Collectively, our results suggest that the use of translational LNT-SeNPs could be further developed as potent strategy for therapy of surgery-induced cognitive impairment. [ABSTRACT FROM AUTHOR]