Neutrophil Membrane-Camouflaged Polyprodrug Nanomedicine for Inflammation Suppression in Ischemic Stroke Therapy

Neuroinflammation has emerged as a major concern in ischemic stroke therapy because it exacebates neurological dysfunction and suppresses neurological recovery after ischemia/reperfusion. Fingolimod hydrochloride (FTY720) is an FDA-approved anti-inflammatory drug which exhibits potential neuroprotective effects in ischemic brain parenchyma. However, delivering a sufficient amount of FTY720 through the blood-brain barrier into brain lesions without inducing severe cardiovascular side effects remains challenging. Here, a neutrophil membrane-camouflaged polyprodrug nanomedicine that can migrate into ischemic brain tissues and in situ release FTY720 in response to elevated levels of reactive oxygen species. This nanomedicine delivers 15.2-fold more FTY720 into the ischemic brain and significantly reduces the risk of cardiotoxicity and infection compared with intravenously administered free drug. In addition, single-cell RNA-sequencing analysis identifies that the nanomedicine attenuates poststroke inflammation by reprogramming microglia toward anti-inflammatory phenotypes, which is realized via modulating Cebpb-regulated activation of NLRP3 inflammasomes and secretion of CXCL2 chemokine. This study offers new insights into the design and fabrication of polyprodrug nanomedicines for effective suppression of inflammation in ischemic stroke therapy. A neutrophil membrane-coated reactive oxygen species (ROS)-responsive polyprodrug nanoparticle (NRN) is reported for the ischemic brain-targeted delivery of fingolimod hydrochloride (FTY720) with minimal side effects. NRNs exhibit enhanced blood-brain barrier penetration, ischemic brain-targeted accumulation, and effective neuroprotection with minimal side effects owing to neutrophil membrane coating and ROS-responsive FTY720 release. image