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Clinically, HAND encompasses a spectrum of neurological impairments ranging from asymptomatic neurocognitive impairment to severe HIV-associated dementia. Despite the widespread use of combination antiretroviral therapy (cART) and significant improvements in the life expectancy of people living with HIV, HAND remains prevalent and continues to pose a major clinical challenge. One of the primary limitations of cART is the limited penetration of many antiretroviral drugs across the blood\u2013brain barrier (BBB), thereby allowing the persistence of viral reservoirs within the CNS and contributing to sustained neuroinflammation and neuronal damage. To address these challenges, novel nanotherapeutic strategies have been developed to enhance the delivery of antiretroviral agents to the brain. These approaches include targeted delivery systems and the co-delivery of therapeutics across the BBB through mechanisms such as receptor-mediated transcytosis and other transport pathways. In this review, we discuss the pathophysiological challenges associated with HAND and recent advances in nanotherapeutic approaches designed to improve treatment efficacy. We also discuss the current state of the art in vitro and in vivo models used to test the efficacy of these advanced therapeutics. Finally, we outline the remaining challenges and future prospects for the development of nanotherapeutics to improve the treatment of HAND.<\/jats:p>","DOI":"10.3390\/biom16050728","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T10:07:47Z","timestamp":1779444467000},"page":"728","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Recent Nanotherapeutic Advancements Against HIV-Associated Neurocognitive Disorders (HAND)"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-3573-3585","authenticated-orcid":false,"given":"Riddhi","family":"Trivedi","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58102, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6073-5533","authenticated-orcid":false,"given":"Avinash","family":"Gothwal","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58102, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2457-7619","authenticated-orcid":false,"given":"Buddhadev","family":"Layek","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58102, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3198-2839","authenticated-orcid":false,"given":"Jagdish","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58102, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,15]]},"reference":[{"key":"ref_1","unstructured":"United Nations (2024). 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