Oral nanoliposomes functionalized with cRGD and polydopamine for enhanced antimalarial efficacy of disulfide bond-modified dihydroartemisinin prodrug

Malaria remains a global health crisis, with <i>Plasmodium</i> 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 <i>Plasmodium</i>-triggered drug release are effective strategies. <i>Plasmodium</i> 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 <i>Plasmodium</i>-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. <i>In vitro</i>, cRPNLs exhibited pH- and GSH-responsive DHA release. <i>Ex vivo</i> 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 <i>in vivo</i> antimalarial pharmacodynamic studies revealed that cRPNLs exhibited significantly higher exposure and <i>Plasmodium</i> 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.