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Neonatal brain injury, such as hypoxic-ischemic encephalopathy (HIE), is a leading cause of infant mortality and long-term neurodevelopmental disabilities. Current clinical therapeutic strategies are limited by the blood-brain barrier (BBB), the complexity of the injury cascade, and the narrow therapeutic window. Nanomedicine has shown potential in preclinical studies for overcoming these barriers by leveraging its unique nanoscale characteristics and engineerability design to load, stabilize, and deliver vulnerable biomacromolecules across the compromised BBB to the lesion site. This review presents the first systematic horizontal comparison and critical evaluation of the major nanoplatforms employed in neonatal brain injury therapy. Based on data derived primarily from animal models, we analyze the heterogeneity across studies in model systems, administration routes, and efficacy endpoints, revealing common challenges in the field regarding long-term safety, manufacturability, and reproducibility. This review aims to provide guidance for selecting appropriate nanoplatforms to facilitate the translational advancement of this field toward clinical applications.