{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T18:30:59Z","timestamp":1789497059045,"version":"build-2803163510"},"reference-count":149,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T00:00:00Z","timestamp":1766102400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibodies"],"abstract":"<jats:p>Nanobodies (single-domain antibodies, VHHs) have emerged as versatile tools for evaluating and treating Alzheimer\u2019s disease (AD). They offer distinct engineering benefits compared with traditional antibodies and small molecules, including small size, stability, and specificity. In AD, nanobodies have been shown in preclinical models to neutralize toxic amyloid-\u03b2 oligomers, inhibit tau generation and aggregation, and modulate neuroinflammation, thereby demonstrating significant therapeutic potential. However, all nanobody applications in AD are discussed strictly as preclinical therapeutic potential rather than established clinical therapies, and direct clinical evidence in patients with AD is still lacking. Advanced engineering strategies, including intranasal and intrathecal routes, receptor-mediated transport, plasma protein binding with albumin, and focused ultrasound to facilitate brain penetration. Additionally, to improve nanobody delivery precision, half-life, and efficacy, strategies such as integrating nanobodies with nanoparticles, dendrimers, liposomes, and viral vectors are being employed. In fact, nanobodies are applied beyond monotherapy across multiple technological platforms to optimize brain delivery and target multiple targets. Nanobodies have been used on bispecific and trispecific antibody platforms, as well as in CRISPR\/Cas9 editing and AI-driven technologies, to expand their applications. Recently, preclinical evidence has been mounting on the efficacy of nanobodies in clearing A\u03b2 and tau, preserving synapses, and normalizing biomarkers. Comparison with FDA-approved anti-A\u03b2 monoclonal antibodies (aducanumab, lecanemab, and donanemab) highlights opportunities and current translational gaps, including safety testing, half-life extension, and delivery optimization. This review critically delineates the current molecular mechanisms, emerging strategies, and delivery platforms, and emphasizes the potential of nanobodies as promising therapeutic and diagnostic molecules in AD therapeutics.<\/jats:p>","DOI":"10.3390\/antib15010001","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T12:59:57Z","timestamp":1766149197000},"page":"1","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Nanobody Therapeutics in Alzheimer\u2019s Disease: From Molecular Mechanisms to Translational Approaches"],"prefix":"10.3390","volume":"15","author":[{"given":"Deepika","family":"Godugu","sequence":"first","affiliation":[{"name":"Department of Pharmacy, University College of Technology Sciences, Osmania University, Hyderabad 500007, Telangana, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3199-6724","authenticated-orcid":false,"given":"Kranthi","family":"Gattu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John\u2019s University, Queens, NY 11439, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parul","family":"Suri","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Jaypee Institute of Information Technology, Noida 201309, Uttar Pradesh, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abel B.","family":"Daartey","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi AK-385-1973, Ghana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5875-2315","authenticated-orcid":false,"given":"Krishna","family":"Jadhav","sequence":"additional","affiliation":[{"name":"Institute for Bioengineering of Catalonia (IBEC), Baldiri Reixac 10-12, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3301-5941","authenticated-orcid":false,"given":"Satish","family":"Rojekar","sequence":"additional","affiliation":[{"name":"Department of Pharmacological Sciences, Icahn School of Medicine, Mount Sinai, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Safiri, S., Ghaffari Jolfayi, A., Fazlollahi, A., Morsali, S., Sarkesh, A., Daei Sorkhabi, A., Golabi, B., Aletaha, R., Motlagh Asghari, K., and Hamidi, S. 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