Self-Assembling Antioxidant Nanoparticles Increase Survival and Reduce Disease Symptoms of Severe Malaria

Severe infectious diseases trigger a rapid increase in cytokines, known as a cytokine storm, accompanied by an excessive rise in reactive oxygen species (ROS), leading to severe damage to tissues and cells. While antioxidants have been used to eliminate ROS, conventional low-molecular-weight (LMW) antioxidants fail to effectively mitigate oxidative stress in infectious diseases due to rapid metabolism, excretion, and potential disruption of the redox balance within normal cells. We developed a novel self-assembling antioxidant nanoparticle, termed a redox nanoparticle (RNP), designed to prevent rapid metabolism and excretion. Furthermore, due to its nanoscale size and poly(ethylene glycol) shell, RNP exhibits limited entry into normal cells, preserving the intracellular redox balance. This study evaluates the impact of RNP on oxidative stress associated with infectious diseases, utilizing a <i>Plasmodium berghei</i>-induced malaria model in mice. After intraperitoneal administration, RNP was absorbed into the bloodstream and remained in circulation for over 24 h. In the malaria model, we observed that once the threshold of erythrocyte parasite infection was exceeded, ROS levels in the blood dramatically increased in untreated infected mice, causing lethal damage. The administration of LMW TEMPOL resulted in only a marginal reduction in ROS, whereas RNP significantly decreased ROS levels, leading to a marked improvement in disease severity and survival. Moreover, the RNP suppressed the oxidation and fragility of erythrocyte membranes caused by infection. These findings highlight the potential of RNP as a breakthrough therapeutic agent for malaria and other infectious diseases characterized by excessive oxidative stress.