LL-37 selectively targets Plasmodium-infected erythrocytes and exhibits antimalarial activity.

Malaria control is challenged by the emergence of resistance to virtually all antimalarial drugs, from the frontline artemisinin to other classes, highlighting the critical need for new therapies. This study demonstrates that the human antimicrobial peptide LL-37 exhibits antiplasmodial activity against both drug-sensitive and drug-resistant parasites in vitro. LL-37 selectively targets infected red blood cells through membrane disruption mediated by phosphatidylserine externalization and cholesterol depletion. Elevated plasma LL-37/CRAMP levels were observed in malaria patients and infected mice, and exogenous LL-37/CRAMP administration reduced parasitemia, improved survival, and modulated pro-inflammatory cytokine levels in a mouse model. CRAMP-deficient mice showed higher susceptibility to infection, underscoring its role in host defense. Our findings reveal a naturally occurring host defense mechanism centered on LL-37/CRAMP, which acts through direct targeting of the infected erythrocyte membrane. However, therapeutic administration after infection establishment showed limited efficacy, likely due to rapid peptide degradation in vivo, and the effective concentrations required for direct killing in vitro are substantially higher than endogenous systemic levels. The reduction in systemic cytokines observed in treated mice is likely primarily attributable to decreased parasite burden rather than direct immunomodulation. Further studies are needed to evaluate stabilized analogs, optimized delivery strategies, and combination approaches before therapeutic applications can be considered.