Adenosine TriphosphateNanoparticles with Blood–BrainBarrier Permeability for Prevention of Cerebral Ischemic Injury viaMitochondrial Homeostasis

Abstract Cerebral ischemia induces selective neuronal death, largely due to mitochondrial dysfunction and ATP depletion. This energy crisis impairs mitophagy, exacerbates oxidative stress, and accelerates neuronal apoptosis. While exogenous ATP supplementation holds promise for restoring mitochondrial function, its clinical application is hindered by rapid in vivo clearance before brain accumulation occurs. Herein, we report positively charged ATP nanoparticles (ATP-N), formulated via electrostatic interactions with chitosan, that facilitate crossing the blood–brain barrier and subsequent adsorptive-mediated transcytosis following intravenous injection, for the prevention of cerebral ischemic injury. Compared with free ATP, ATP-N exhibited a prolonged circulation time and enhanced brain accumulation. In a mouse model of cerebral ischemia, ATP-N effectively replenished intracellular ATP, restored mitochondrial membrane potential, and activated mitophagy, leading to reduced neuronal apoptosis and attenuated ischemic damage. These findings highlight ATP-N as a promising, minimally invasive therapeutic strategy to prevent ischemic brain injury, enabling rapid and efficient ATP delivery to restore mitochondrial function and promote neuronal survival.