Intranasal Delivery of si‐circHECTD1@mLNP for Cerebral Ischemic Stroke Therapy via Modulation of the Neuroinflammatory Microenvironment

Acute ischemic stroke (AIS) is a leading cause of death and long-term disability globally, with current treatment options offering limited efficacy in improving neurological recovery. Building upon our earlier discovery, we previously characterized circHECTD1, a circular RNA generated from exons 23-24 of the HECTD1 gene, as a critical regulator of ischemic brain injury. Despite its therapeutic potential, targeted interventions against circHECTD1 have yet to be developed. In this work, we report a mannose-modified lipid nanoparticle for targeted delivery of si-circHECTD1 (si-circHECTD1@mLNP) to evaluate its therapeutic impact on neuroinflammation, infarct volume, and sensorimotor functions of stroke mice. In a murine transient middle cerebral artery occlusion (tMCAO) model, we found that nose-to-brain administration of si-circHECTD1@mLNPs selectively inhibited circHECTD1 expression, subsequently alleviated neuroinflammation, suppressed both astrocytic and microglial activation, reduced infarct volume, and ultimately improved functional recovery. Transcriptomic profiling further demonstrates not only downregulation of neuroinflammation-associated pathways but also upregulation of neuro-restorative programs. Our findings confirm circHECTD1 as a pathogenic mediator and therapeutic target in AIS, while establishing a versatile mLNP platform for RNA therapy to improve neurological outcomes of AIS.