The interstitial space,a widespread fluid-filled compartment throughout the body,is related to many pathophysiological alterations and diseases,attracting increasing attention.The vital role of interstitial space in malaria infection and treatment has been neglected current research efforts.We confirmed the reinfection capacity of parasites sequestrated in interstitial space,which replenish the mechanism of recurrence.Malaria parasite-infected mice were treated with artemisinin-loaded liposomes through the interstitial space and exhibited a better therapeutic response.Notably,compared with oral administration,interstitial administration showed an unexpectedly high activation and recruitment of immune cells,and resulted in better clearance of sequestered parasites from organs,and enhanced pathological recovery.The interstitial route of administration prolongs the blood circulation time of artemisinin and increases its plasma concentration,and may compensate for the inefficiency of oral administration and the nanotoxicity of intravenous administration,providing a potential strategy for infectious disease therapy.