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While nanoparticle\u2010based drug delivery systems (NDDS) offer theoretical advantages over conventional therapies, their clinical translation in PDAC has been severely limited. The dense desmoplastic stroma, elevated interstitial fluid pressure, and hypovascularity effectively neutralize the enhanced permeability and retention (EPR) effect, restricting passive nanoparticle penetration. Consequently, the therapeutic paradigm is shifting from indiscriminate stromal depletion\u2014which paradoxically accelerates metastasis\u2014to stromal normalization and immune microenvironment reprogramming. This review comprehensively evaluates advanced NDDS platforms, highlighting transcytosis\u2010triggering active targeting, stimuli\u2010responsive carriers, and multimodal theranostic systems designed to bypass physical barriers and convert immunologically \u201ccold\u201d tumors to \u201chot.\u201d Furthermore, we analyze the expanding role of artificial intelligence (AI) and machine learning in predicting synergistic drug combinations and optimizing nanoparticle physicochemical properties. Crucially, we critique current epistemic limitations in AI\u2010driven nanomedicine, particularly data sparsity and the reliance on 2D preclinical models, emphasizing the necessity of 3D patient\u2010derived organoid validation. By integrating rational NDDS design with AI and biomarker\u2010driven strategies, this review maps the essential pathways toward personalized nanotherapeutics for PDAC.<\/jats:p>","DOI":"10.1002\/med.70105","type":"journal-article","created":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T07:33:09Z","timestamp":1788593589000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["AI\u2010Driven Rational Design of Nanotherapeutics for Pancreatic Ductal Adenocarcinoma"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4000-1836","authenticated-orcid":false,"given":"Seohyun","family":"Choo","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering Dongguk University Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4400-8001","authenticated-orcid":false,"given":"Kaeun","family":"Chae","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Dongguk University Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jueun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Dongguk University Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1483-3890","authenticated-orcid":false,"given":"Inseon","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Dongguk University Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9654-8577","authenticated-orcid":false,"given":"Seunghun S.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Dongguk University Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,5]]},"reference":[{"issue":"9791","key":"e_1_2_11_2_1","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/S0140-6736(10)62307-0","article-title":"Pancreatic Cancer","volume":"378","author":"Vincent A.","year":"2011","journal-title":"Lancet"},{"issue":"1","key":"e_1_2_11_3_1","doi-asserted-by":"crossref","DOI":"10.1038\/nrdp.2016.22","article-title":"Pancreatic Cancer","volume":"2","author":"Kleeff J.","year":"2016","journal-title":"Nature Reviews Disease Primers"},{"key":"e_1_2_11_4_1","doi-asserted-by":"crossref","first-page":"3379","DOI":"10.2147\/IJN.S504503","article-title":"Extensive Review of Nanomedicine Strategies Targeting the Tumor Microenvironment in PDAC","volume":"20","author":"Liu X.","year":"2025","journal-title":"International Journal of Nanomedicine"},{"issue":"24","key":"e_1_2_11_5_1","doi-asserted-by":"crossref","first-page":"6175","DOI":"10.3390\/cancers13246175","article-title":"Nanomedicine in Pancreatic Cancer: Current Status and Future Opportunities for Overcoming Therapy Resistance","volume":"13","author":"Greene M. 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