Development and evaluation of novel zein-based artemisinin sustained-release formulation for treating drug-resistant malaria

Artemisinin antimalarial drugs initially exhibited remarkable efficacy against Plasmodium falciparum. However, their poor solubility and low bioavailability necessitate high doses and lead to an extremely short in vivo half-life. These limitations not only drive the emergence of drug-resistant Plasmodium strains but also compromise long-term therapeutic outcomes. Herein, we report a zein-based sustained release formulation, wherein zein, a natural maize protein, serves as a biocompatible nanocarrier to effectively encapsulate artemisinin (ART). Notably, this nanocarrier formulation achieves a 200-fold enhancement in ART’s water solubility, addressing a key bottleneck of ART-based therapies. In vitro assays confirm that the zein-based formulation allows for the sustained release of ART, which could help maintain therapeutic concentrations over extended periods and displayed different release rates and good dispersibility in both acid and basic environments. Importantly, in vitro evaluations also demonstrate that the nanoformulation exerts potent inhibitory effects against ART-resistant P. falciparum strains in both ring survival assay and recrudescence assay, attributed to the sustained maintenance of effective ART concentrations. In vivo studies, utilizing both rodent malaria models and humanized erythrocyte mouse models, further validate the nanoformulation’s therapeutic potential. The zein nanocarrier significantly prolongs ART’s in vivo half-life via its sustained-release capability, thereby maintaining effective blood concentrations over an extended duration. Compared to free ART, the nanoformulation exhibits superior efficacy in reducing parasitemia, preventing malaria recrudescence, and, most notably, overcoming ART resistance in drug-resistant Plasmodium infections. Collectively, these findings establish the zein-based nanocarrier as a promising strategy to optimize ART-based therapies by addressing solubility and pharmacokinetic limitations while effectively combating drug-resistant malaria.