{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:10:38Z","timestamp":1792789838831,"version":"4.5.0"},"reference-count":185,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T00:00:00Z","timestamp":1769904000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>The blood\u2013brain barrier (BBB) is a major obstacle to the development of brain-targeted drug delivery systems, restricting greater than 98% of small molecules (&lt;500 Da) and virtually all large-molecule drugs from entering the brain tissues from the bloodstream, resulting in suboptimal drug doses and therapeutic failure in the treatment of Alzheimer\u2019s disease (AD). However, the advent of nanotechnology has provided significant solutions to the BBB challenges, enabling particle size reduction, enhanced drug solubility, reduced premature drug degradation, extended and sustained drug release, enhanced drug transport across the BBB, increased drug target specificity and enhanced therapeutic efficacy. In corollary, a library of brain-targeted surface-functionalized nanotherapeutics has been widely reported in the current literature. These promising in vitro, in vivo and pre-clinical results from the existing literature provide quantitative evidence for the relative clinical utility of each of the techniques, indicating remarkable capacity for brain-targeted carrier systems; many of them are still being tested in human clinical trials. However, despite the recorded research successes in drug transport across the BBB, there are currently no clinically proven medications that can slow or reverse the progression of AD because most of the novel therapeutics have not been successful during the clinical trials. Therefore, the main option for the treatment of AD is symptomatic treatment using cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists. Although these therapies help to alleviate symptoms of AD and improve patients\u2019 quality of life, they neither slow the progression of disease nor cure it. Thus, an effective disease-modifying therapy for the treatment of AD is an unmet clinical need. It is apparent that a deeper understanding of the structural complexity and controlling dynamic functions of the BBB in tandem with a comprehensive elucidation of AD pathogenesis are crucial to the development of novel nanocarriers for the effective treatment of AD. Therefore, this narrative review describes the contextual analysis of several promising strategies that enhance brain-targeted drug delivery across the BBB in AD treatment and recent research efforts on two major AD biomarkers that have revolutionized AD diagnosis, amyloid-beta plaques and phosphorylated tau protein tangle, as potential targets in AD drug development. This has led to the Food and Drug Administration (FDA)\u2019s approval of two intravenous (IV) anti-amyloid monoclonal antibodies, Lecanemab (Leqembi\u00ae) and Donanemab (Kisunla\u00ae), which were developed based on the A\u03b2 cascade hypothesis for the treatment of early AD. This review also discusses the recent shift in the A\u03b2 cascade hypothesis to A\u03b2 oligomer (conformer), a soluble intermediate of A\u03b2, which is the most toxic mediator of AD and could be the most potent drug target in the future for a more accurate and effective drug development model for the treatment of AD. Furthermore, various promising nanoparticle-based drug carriers (therapeutic nanoparticles) that were developed from intensive research are discussed, including their clinical utility, challenges and prospects in the treatment of AD. Overall, it suffices to state that the advent of nanotechnology provided several innovative techniques for overcoming the BBB and improving drug delivery to the brain; however, their long-term biosafety is a relevant concern.<\/jats:p>","DOI":"10.3390\/pharmaceutics18020192","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T09:48:08Z","timestamp":1770025688000},"page":"192","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Recent Advances in Nanoparticle-Based Drug Delivery Strategies to Cross the Blood\u2013Brain Barrier in Targeted Treatment of Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-6219-3228","authenticated-orcid":false,"given":"Hoa","family":"Le","sequence":"first","affiliation":[{"name":"Faculty of Pharmaceutics and Pharmaceutical Technology, Hanoi University of Pharmacy, Hanoi 100000, Vietnam"},{"name":"Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, Saint Joseph\u2019s University, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7973-1302","authenticated-orcid":false,"given":"Giang T. T.","family":"Vu","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutics and Pharmaceutical Technology, Hanoi University of Pharmacy, Hanoi 100000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7606-2588","authenticated-orcid":false,"given":"Amos","family":"Abioye","sequence":"additional","affiliation":[{"name":"School of Pharmacy, College of Pharmacy and Health Sciences, Belmont University, Nashville, TN 37212, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adeboye","family":"Adejare","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, Saint Joseph\u2019s University, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/S0140-6736(15)01124-1","article-title":"Alzheimer\u2019s disease","volume":"388","author":"Scheltens","year":"2016","journal-title":"Lancet"},{"key":"ref_2","unstructured":"Alzheimer\u2019s Association Report (2025). 2025 Alzheimer\u2019s disease facts and figures. 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