Engineered Brain‐Targeted Exosomes Delivering FGF1 for Sustained Glycemic Regulation and Multitarget Neurovascular Protection in Diabetic Stroke

Diabetic stroke is characterized by a hyperglycemic and pro‐inflammatory microenvironment that exacerbates neurovascular dysfunction. However, the blood–brain barrier (BBB) remains a formidable obstacle, restricting the delivery of most therapeutic molecules. To address this, we developed a non‐invasive treatment strategy using engineered exosomes. Specifically, we fabricated FGF1‐loaded exosomes functionalized with the rabies virus glycoprotein (RVG) peptide (FGF1‐RVG Exo). This platform facilitates selective, neuron‐targeted delivery of FGF1 to the ischemic penumbra via RVG‐mediated transcytosis. In a diabetic stroke mouse model, FGF1‐RVG Exo exhibited superior pharmacological efficacy compared to free FGF1, achieving robust therapeutic outcomes with only once‐weekly administration. Notably, a single dose during the acute phase elicited a sustained hypoglycemic effect lasting up to two weeks and effectively ameliorated systemic insulin resistance. Locally, the accumulation of exosomes within the lesion led to a significant reduction in infarct volume and cell apoptosis, while promoting neovascularization and the recovery of motor and cognitive functions. This brain‐targeted strategy achieves a peripheral–central synergistic modulation, addressing the multi‐target requirements of diabetic stroke management. Collectively, our findings provide a novel paradigm for treating diabetic ischemic stroke and a potent strategy for the targeted delivery of growth factors to the central nervous system.