Blood-brain barrier-penetrant nanotherapy inhibits haem oxygenase-1-mediated ferroptosis for post-resuscitation neuroprotection

Cardiac arrest (CA) induces global ischaemia-reperfusion (I/R) injury that results in extensive neuronal damage and high rates of mortality and cognitive impairment, yet effective neuroprotective therapies remain lacking. A major barrier to intervention is the blood-brain barrier (BBB), which restricts drug access to injured brain tissue. Here, we present a BBB-penetrant nanotherapy that combines zwitterionic poly (tertiary amine oxide)-based micelles (OPDEA) with pleiotropic neuroprotectant artesunate (Art). The resulting formulation (OAMs) efficiently crosses the intact BBB via adsorptive-mediated transcytosis and accumulates in hippocampal neurons and microglia. Using in vitro hypoxia-reoxygenation and in vivo male mouse CA/cardiopulmonary resuscitation (CPR) models, we identify haem oxygenase-1 (HMOX1)-mediated ferroptosis as a key mechanism of post-resuscitation neuronal injury. OAMs suppress HMOX1 activity, restore iron homeostasis, and alleviate lipid peroxidation, thereby preserving mitochondrial function and neuronal viability. This work defines the HMOX1-ferroptosis axis as a tractable therapeutic target and positions OPDEA micelles as a BBB-penetrant nanoplatform for neuroprotection after CA and potentially other central nervous system diseases. Limited drug delivery across the blood-brain barrier (BBB) hinders the therapy of post-resuscitation brain injury after cardiac arrest. Here, the authors report zwitterionic poly (tertiary amine oxide)-based micelles that cross the BBB via transcytosis and deliver artesunate to suppress haem oxygenase-1-driven ferroptosis, restore iron homeostasis and provide neuroprotection after resuscitation.