ZIF-8 with encapsulated dihydroartemisinin in a drug delivery system for protection against <i>Plasmodium berghei</i> ANKA-induced experimental cerebral malaria in C57BL/6N mice

Cerebral malaria (CM), primarily caused by <i>Plasmodium falciparum</i>, is the primary cause of malaria-related fatalities. CM treatment faces significant challenges due to limited therapeutic options and the emergence of antimalarial drug resistance. Dihydroartemisinin (DHA) is the first-line therapeutic agent for malaria. However, it encounters limitations such as poor solubility, inadequate selectivity, and rapid elimination. Here, we introduced a facile and effective approach using zeolite imidazolium framework-8 (ZIF-8) encapsulated with DHA (DHA@ZIF-8) and assessed its therapeutic efficacy in an experimental cerebral malaria model. The DHA@ZIF-8 demonstrated excellent drug-loading capacity, high stability, prolonged drug release, and improved targeted elimination of <i>Plasmodium</i> parasites within infected red blood cells (iRBCs). This minimized damage to brain microvascular endothelial cells (BMECs) and protected organs from injury, increasing the survival time of the infected mice. Compared to free DHA, DHA@ZIF-8 exhibited better antimalarial efficacy and almost no side effects. This study highlights ZIF-8's potential as a reliable, stable, and efficient drug delivery vector for DHA to improve CM therapy.IMPORTANCEFor the treatment of human malaria, artemisinin-based drugs remain the first-line treatment option. However, their utility is constrained by their short half-life <i>in vivo</i>. Consequently, extending the duration for drug efficacy in the body is a critical issue that needs to be addressed. Metal-organic frameworks are a promising choice for drug loading. In the present study, DHA@ZIF-8 and DHA@MOF were constructed and characterized and were assessed in an experimental cerebral malaria model of C57BL/6 N mice induced by <i>Plasmodium berghei</i> ANKA strain. Data show that DHA@ZIF-8 has a worthy therapeutic effect on experimental cerebral malaria. It will offer a new option for human cerebral malaria (HCM) treatment.