Exogenous plant miRNAs, particularly MIR168a, are present in the sera and tissues of various animals, primarily acquired through food intake. This study demonstrates that MIR168a, abundant in rice, can bind to the human/mouse LDLRAP1 mRNA, inhibit LDLRAP1 expression in the liver, and reduce LDL removal from mouse plasma. These findings indicate that exogenous plant miRNAs can regulate mammalian gene expression. The study shows that plant miRNAs are stable in serum and tissues, with MIR168a being resistant to periodate oxidation, confirming their plant origin. MIR168a can pass through the gastrointestinal tract and enter the bloodstream and organs, where it cross-kingdomly regulates LDLRAP1 expression. In vitro and in vivo experiments show that MIR168a binds to exon 4 of LDLRAP1, reducing its protein levels. The study also demonstrates that MIR168a in MVs derived from intestinal epithelial cells can effectively deliver the miRNA to recipient cells, where it regulates LDLRAP1 expression. Anti-MIR168a ASO treatment reversed the reduction of LDLRAP1 protein caused by rice feeding, confirming the role of MIR168a in regulating LDLRAP1. The study highlights the potential of exogenous plant miRNAs to influence mammalian biology through cross-kingdom regulation.Exogenous plant miRNAs, particularly MIR168a, are present in the sera and tissues of various animals, primarily acquired through food intake. This study demonstrates that MIR168a, abundant in rice, can bind to the human/mouse LDLRAP1 mRNA, inhibit LDLRAP1 expression in the liver, and reduce LDL removal from mouse plasma. These findings indicate that exogenous plant miRNAs can regulate mammalian gene expression. The study shows that plant miRNAs are stable in serum and tissues, with MIR168a being resistant to periodate oxidation, confirming their plant origin. MIR168a can pass through the gastrointestinal tract and enter the bloodstream and organs, where it cross-kingdomly regulates LDLRAP1 expression. In vitro and in vivo experiments show that MIR168a binds to exon 4 of LDLRAP1, reducing its protein levels. The study also demonstrates that MIR168a in MVs derived from intestinal epithelial cells can effectively deliver the miRNA to recipient cells, where it regulates LDLRAP1 expression. Anti-MIR168a ASO treatment reversed the reduction of LDLRAP1 protein caused by rice feeding, confirming the role of MIR168a in regulating LDLRAP1. The study highlights the potential of exogenous plant miRNAs to influence mammalian biology through cross-kingdom regulation.