This study reports that exogenous plant microRNAs (miRNAs) are present in the sera and tissues of various animals, primarily acquired through oral intake. Specifically, MIR168a, abundant in rice, is highly enriched in the sera of Chinese subjects. In vitro and in vivo studies demonstrate that MIR168a binds to the human/mouse low-density lipoprotein receptor adapter protein 1 (LDLRAP1) mRNA, inhibits LDLRAP1 expression in the liver, and reduces LDL removal from mouse plasma. These findings indicate that exogenous plant miRNAs in food can regulate target gene expression in mammals, highlighting a novel cross-kingdom regulatory mechanism involving microvesicles (MVs). The study also shows that mature single-stranded plant miRNAs are stable and resistant to digestion in the gastrointestinal tract, suggesting they can be efficiently absorbed and transported to other tissues. Furthermore, the functional form of MIR168a in vivo is associated with AGO2 in MVs, indicating a novel pathway for cross-kingdom regulation through MV-mediated delivery.This study reports that exogenous plant microRNAs (miRNAs) are present in the sera and tissues of various animals, primarily acquired through oral intake. Specifically, MIR168a, abundant in rice, is highly enriched in the sera of Chinese subjects. In vitro and in vivo studies demonstrate that MIR168a binds to the human/mouse low-density lipoprotein receptor adapter protein 1 (LDLRAP1) mRNA, inhibits LDLRAP1 expression in the liver, and reduces LDL removal from mouse plasma. These findings indicate that exogenous plant miRNAs in food can regulate target gene expression in mammals, highlighting a novel cross-kingdom regulatory mechanism involving microvesicles (MVs). The study also shows that mature single-stranded plant miRNAs are stable and resistant to digestion in the gastrointestinal tract, suggesting they can be efficiently absorbed and transported to other tissues. Furthermore, the functional form of MIR168a in vivo is associated with AGO2 in MVs, indicating a novel pathway for cross-kingdom regulation through MV-mediated delivery.