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Disruption of its normal functioning has been associated with the onset of various metabolic disorders in the body that arise from several genetic, immunological, and environmental factors or their combination. To combat this, developing treatment strategies that modulate the activity of the hypothalamus could be advantageous. Here, understanding the hypothalamus\u2019s complex structure and function within the context of regulation of energy balance is important to identify treatment targets and to explore opportunities to modulate key metabolic pathways. Moreover, the unique sensitive position of the hypothalamus in the brain necessitates that treatment strategies that are developed are highly effective and specific, and do not cause any untoward effects at neighboring regions of the brain. This is further complicated by its protection through the blood-brain barrier (BBB) that highly regulates the entry of materials from the periphery, allowing entry of molecules only under specific conditions. In this regard, advanced multifunctional nanoparticulate drug-delivery systems can be of benefit as they have been explored for brain specific delivery. For this, nanoparticle chemistry, specific ligand expression, BBB penetration capability, biocompatibility, and immunogenicity among other physicochemical properties are important parameters that govern brain specific delivery. In this review, the role of hypothalamus in regulating energy metabolism, its structure and function and the effect of dysfunction on the onset of metabolic disorders are summarized. Furthermore, the use of nanoparticles for brain targeting and hypothalamic regulation, such as small extracellular vesicles targeting AMP-activated protein kinase (AMPK), along with the future of nanoparticle-based modulation of the hypothalamus is also discussed.<\/jats:p>","DOI":"10.1007\/s11154-026-10022-z","type":"journal-article","created":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T06:45:07Z","timestamp":1772606707000},"page":"705-729","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Hypothalamic wars: the last nanodelivery"],"prefix":"10.1007","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4752-2813","authenticated-orcid":false,"given":"Sajid","family":"Fazal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7285-690X","authenticated-orcid":false,"given":"Jane Jose","family":"Vattathara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7823-1648","authenticated-orcid":false,"given":"Miguel","family":"L\u00f3pez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,4]]},"reference":[{"key":"10022_CR1","doi-asserted-by":"publisher","first-page":"155999","DOI":"10.1016\/j.metabol.2024.155999","volume":"160","author":"H Zhang","year":"2024","unstructured":"Zhang H, Zhou XD, Shapiro MD, Lip GYH, Tilg H, Valenti L, Somers VK, Byrne CD, Targher G, Yang W, et al. 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