Reversing artemisinin resistance by leveraging thermo-responsive nanoplatform to downregulating GSH

Artemisinin (ART) resistance has been an emerging clinical problem, severely compromising antimalarial efficacy and threatening the global malaria elimination campaign. Albeit intensive studies about the molecular mechanism for ART resistance are under way, no effective therapeutic targets for reversing resistance have been applied. Here, we explore glutathione (GSH) as a therapeutic target to develop a thermo-responsive nanoplatform to specifically co-deliver ART and GSH synthesis inhibitor (L-buthionine sulfoximine, BSO) in a sustained manner, effectively reversing ART resistance in vivo. By combining with BSO, ART exerts increased antimalarial activity with reduced half-maximal inhibitory concentration (IC50) by 7.43-fold in ART-resistant strains. This work reveals that the GSH in ART-resistant parasites can be a promising therapeutic target for reversing ART resistance, paving the way for developing drug candidates and intelligent nanomedicines in malaria therapy.