A Fe-incorporated bioreactor platform exhibiting antimalarial activity and enhanced response to artemisinin.

While malaria parasites rely on labile Fe2+ pools for survival, excess Fe2+ acts as a Fenton reagent, inducing cytotoxicity via reactive oxygen species and membrane disruption, highlighting iron homeostasis as a key therapeutic vulnerability. To test the feasibility of iron ions in inhibiting Plasmodium parasites, we developed Fe2+-loaded polydopamine nanoparticles (PDA@Fe/P) that exploit the parasite's iron-dependent vulnerabilities through dual mechanisms: (i) sustained Fe2+ release triggers Fenton reactions, generating cytotoxic hydroxyl radicals that overwhelm antioxidant defenses, and (ii) restoration of artemisinin (ART) activation in resistant parasites by supplementing the diminished Fe2+ pool. In vitro testing against five P. falciparum strains (including chloroquine- and ART-resistant variants) demonstrated potent, antimalarial activity, with efficacy 20-fold higher than free FeCl2 due to enhanced solubility and controlled release. While in vivo studies in P. berghei-infected mice showed transient parasite suppression without toxicity, the relatively high IC50 precludes standalone use. Crucially, PDA@Fe/P enhanced the activity of ART against P. falciparum strain with partial ART resistance conferred by Kelch13 mutation, by counteracting mutation-induced impairments in hemoglobin endocytosis and heme bioavailability-key determinants of ART activation. Analysis of lipid peroxidation levels revealed that Fe2+ delivered via PDA@Fe/P amplifies oxidative stress responses in resistant parasites, indicating its ability to enhance the sensitivity of ART-resistant strains to ART. Our findings establish iron-based delivery strategies as a promising approach to potentiate existing antimalarials and combat resistance through the targeted disruption of redox homeostasis.