Malaria remains a global health crisis, with resistance underscoring the urgent need for advanced drug delivery strategies. To overcome the limitations of oral antimalarials, such as hepatic first-pass metabolism and insufficient drug accumulation in parasites, intestinal M cell-mediated lymphatic transport and -triggered drug release are effective strategies. parasites maintain a weakly acidic intracellular environment with high levels of glutathione (GSH). Polydopamine (PDA) remains stable in the gastrointestinal tract and degrades in the parasite's weakly acidic, GSH-rich environment, making PDA nanoliposomes (PNLs) a promising oral delivery system for -responsive drug release. Additionally, cyclic arginine-glycine-aspartic acid (cRGD) can specifically target intestinal M cells, promoting lymphatic transport and thereby reducing the first-pass effect. We developed cRGD- and PDA-modified nanoliposomes (cRPNLs) to address the challenges associated with oral administration and loaded them with a disulfide bond (-SS-)-modified dihydroartemisinin (DHA) prodrug (DSSC) to simultaneously deplete GSH and induce lethal oxidative stress, thereby offering an enhanced antimalarial mechanism. , cRPNLs exhibited pH- and GSH-responsive DHA release. fluorescent imaging confirmed that cRPNLs targeted Peyer's patches with minimal distribution in the liver. Crucially, both PNLs and cRPNLs reduced GSH levels in infected erythrocytes and elevated ROS by 2.0-fold, outperforming unmodified DHA. Pharmacokinetic and antimalarial pharmacodynamic studies revealed that cRPNLs exhibited significantly higher exposure and inhibition rates compared to PNLs and free DHA. These results highlight cRPNLs as a potent oral nanoplatform that combines M cell-mediated lymphatic uptake with parasite-triggered drug release, significantly improving antimalarial efficacy.