The poor central nervous system leukemia (CNSL) medical efficacy of standard doses of chemotherapy is principally attributed to the restricted permeability of chemotherapy brokers brought on by the blood-brain barrier (BBB). Successfully enhancing the buildup of medicine throughout the BBB within the central nervous system is likely one of the key challenges in bettering affected person compliance and medical efficacy of CNSL. Right here, we discover that the VP1 protein, the useful module of the John Cunningham (JC) virus, can safely penetrate the BBB by a sialic acid receptor-mediated transcytosis mechanism. Primarily based on this, we develop a JC virus-mimicking nanodrug supply platform based mostly on VP1 protein-conjugated self-assembled nanoparticles (MFHV), which may energetic goal and cross the BBB by way of a receptor-mediated transcytosis for protected and efficient low-dose chemotherapy in opposition to CNSL after systemic administration. The outcomes show that such a platform can penetrate the BBB by the twin mechanism of clathrin-mediated endocytosis and micropinocytosis pathway. When additional synergistic with ferroptosis and histamine metabolism, the long-term survivors of low-dose MTX are considerably enhanced by 83.3 % and 56.7 % in two CNSL mice fashions. Collectively, this research takes a brand new perspective on pure residing supplies and molecule focusing on of the BBB to current a promising technique for low-dose chemotherapy in opposition to CNSL with security and efficacy, which could present a clinically translatable choice for the prevention and therapy of CNSL.
