Bio-inspired spatiotemporal cascade reaction liposome for ferroptosis treatment following subarachnoid hemorrhage

Subarachnoid hemorrhage (SAH) is a type of stroke mainly caused by the bursting of brain aneurysms, releasing iron ions into the subarachnoid space and subsequently inducing ferroptosis. Despite the utilization of various ferroptosis-inhibiting pharmacological agents to enhance neurological outcomes post-SAH, challenges such as inadequate targeting and suboptimal drug utilization persist. In response to these limitations, we have developed a novel spatiotemporal cascade reaction liposome that recombinant proteins incorporating neuron-targeting peptides and the functional structural domain of ferroptosis suppressor protein 1 (FSP1) were immobilized on the external surface of liposomes, which were internally loaded with coenzyme Q10 (CoQ10) to construct FSP1-Lipo-CoQ10.The purpose of this study is to investigate the neuroprotective effects of FSP1-Lipo-CoQ10 following SAH. As a result, FSP1-loaded liposomes enable targeted delivery to neurons in the lesion area and increase FSP1 levels on the cell membrane. Among the three liposomal formulations, FSP1-Lipo-CoQ10 demonstrated the most potent anti-ferroptosis effects and the greatest improvement in neurological function. FSP1-Lipo-CoQ10 provides a new approach for the therapeutic management of ferroptosis post-SAH and ameliorates associated pathological conditions. Schematic illustration of bio-inspired spatiotemporal cascade reaction liposome. This study involved the development of a liposome-encapsulated CoQ10 formulation, integrated with R-FSP1 (containing a neuron-targeting peptide and an FSP1 anti-ferroptotic structural domain), on the exterior surface, collectively termed FSP1-Lipo-CoQ10. To establish an SAH model, a plastic needle was introduced into the ECA at the juncture leading to the intracranial vessel, followed by puncture of the intracranial vessels. The administration of FSP1-Lipo-CoQ10 via carotid artery injection facilitates its entry into the nervous system at sites of intracranial vascular injury, enabling targeted delivery to neurons. Upon neuronal uptake of FSP1-Lipo-CoQ10, FSP1 anchors to the cell membrane and activates CoQ10 cycling to inhibit ferroptosis.