{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T09:44:30Z","timestamp":1780393470427,"version":"3.54.1"},"reference-count":158,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Smart Growth, Digitalization and Financial Instruments Program","award":["330783"],"award-info":[{"award-number":["330783"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) remains a major unmet medical challenge due to its complex pathology, high interpatient heterogeneity and frequent association with systemic comorbidities. Conventional pharmacotherapy is limited by poor blood\u2013brain barrier permeability, off-target effects and reduced efficacy in polymedicated elderly populations. Smart drug-delivery systems (DDS), particularly nanotechnology-based platforms, have emerged as promising strategies to enhance brain targeting, optimize controlled drug release and mitigate systemic toxicity. This review examines recent advances in intelligent DDS for AD, with a focus on nanocarriers designed to modulate amyloid aggregation, neuroinflammation, oxidative stress and cholinergic dysfunction. Special attention is given to the impact of the most common comorbid conditions on DDS pharmacokinetics, safety and clinical performance. Furthermore, the challenges associated with clinical translation, such as long-term safety, immunogenicity, manufacturing scalability and regulatory harmonization, are critically discussed. In this context, versatile controlled release platforms that integrate rational design, predictive modeling and Quality by Design-driven manufacturing are highlighted as key enablers of translational success. By bridging intelligent formulation design with scalable production and regulatory readiness, advanced controlled release systems offer a pathway toward precision and patient-centered therapies. Such platforms hold significant potential to accelerate the safe integration of smart DDS into Alzheimer\u2019s disease management and broader neurotherapeutic applications.<\/jats:p>","DOI":"10.3390\/life16030510","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T12:49:24Z","timestamp":1773924564000},"page":"510","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Smart Drug-Delivery Approaches for Enhanced Management of Comorbid Conditions in Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4440-9628","authenticated-orcid":false,"given":"Gabriela-Dumitrita","family":"Stanciu","sequence":"first","affiliation":[{"name":"Advanced Research and Development Center for Experimental Medicine \u201cProf. Ostin C. Mungiu\u201d\u2014CEMEX, Grigore T. Popa University of Medicine and Pharmacy Iasi, 700454 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6396-0105","authenticated-orcid":false,"given":"Ivona","family":"Costachescu","sequence":"additional","affiliation":[{"name":"Advanced Research and Development Center for Experimental Medicine \u201cProf. Ostin C. Mungiu\u201d\u2014CEMEX, Grigore T. Popa University of Medicine and Pharmacy Iasi, 700454 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6506-8831","authenticated-orcid":false,"given":"Camelia","family":"Dascalu","sequence":"additional","affiliation":[{"name":"Advanced Research and Development Center for Experimental Medicine \u201cProf. Ostin C. Mungiu\u201d\u2014CEMEX, Grigore T. Popa University of Medicine and Pharmacy Iasi, 700454 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9868-1999","authenticated-orcid":false,"given":"Bogdan-Ionel","family":"Tamba","sequence":"additional","affiliation":[{"name":"Advanced Research and Development Center for Experimental Medicine \u201cProf. Ostin C. Mungiu\u201d\u2014CEMEX, Grigore T. Popa University of Medicine and Pharmacy Iasi, 700454 Iasi, Romania"},{"name":"Clinical Pharmacology and Algesiology, Department of Pharmacology, Grigore T. Popa University of Medicine and Pharmacy Iasi, 700454 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,19]]},"reference":[{"key":"ref_1","unstructured":"Clare, L., and Jeon, Y.H. (2025). 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