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Here we report a multi\u2010stimuli\u2010responsive nanocomposite, Lignin@GO@ZIF\u20108, that co\u2010delivers 5\u2010Fluorouracil (5\u2010FU) and metformin and couples pH\u2010 and redox\u2010responsive release. We integrate machine learning (ML) to guide formulation: trained on 500 formulation property pairs with cross\u2010validation and a held\u2010out test set, XGBoost achieved the highest predictive performance (\n                    <jats:italic>\n                      R\n                      <jats:sup>2<\/jats:sup>\n                      =\n                    <\/jats:italic>\n                    0.86\u20130.89) for drug loading, encapsulation efficiency, and release rate, with influential features including the ZIF\u20108 fraction, graphene oxide (GO) content, particle size, zeta potential, pH, and glutathione concentration. ML\u2010optimized Lignin@GO@ZIF\u20108 exhibited improved loading and tunable release relative to pre\u2010optimized controls. In vitro, the platform sustained drug release and produced potent anticancer activity, reducing LNCaP viability to 18 \u00b1 3% at 72\u00a0h, while showing low cytotoxicity toward non\u2010malignant cells. These results support a data\u2010driven framework for rational design of multifunctional, stimuli\u2010responsive nanomedicine platforms and may help inform future translational strategies for prostate cancer.\n                  <\/jats:p>","DOI":"10.1002\/smll.202513085","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T14:49:52Z","timestamp":1770043792000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["AI\u2010Guided Design of pH\u2010 and Redox\u2010Responsive Lignin@GO@ZIF\u20108 Nanocarriers for Targeted Co\u2010Delivery of 5\u2010Fluorouracil and Metformin in Prostate Cancer Therapy"],"prefix":"10.1002","volume":"22","author":[{"given":"Babbiker Mohammed Taher","family":"Gorish","sequence":"first","affiliation":[{"name":"International Joint Laboratory On Synthetic Biology and Biomass Biorefinery Biofuels Institute School of Emergency Management School of the Environment and Safety Engineering Jiangsu University  Zhenjiang P. R. China"},{"name":"Jiangsu Collaborative Innovation Center of Technology and Material of Water Treatment Suzhou University of Science and Technology  Suzhou P. R. China"},{"name":"Department of Microbiology College of Medical Laboratory Science Omdurman Islamic University  Khartoum Sudan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waha Ismail Yahia","family":"Abdelmula","sequence":"additional","affiliation":[{"name":"International Joint Laboratory On Synthetic Biology and Biomass Biorefinery Biofuels Institute School of Emergency Management School of the Environment and Safety Engineering Jiangsu University  Zhenjiang P. R. China"},{"name":"Jiangsu Collaborative Innovation Center of Technology and Material of Water Treatment Suzhou University of Science and Technology  Suzhou P. R. 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China"},{"name":"Jiangsu Collaborative Innovation Center of Technology and Material of Water Treatment Suzhou University of Science and Technology  Suzhou P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Yahu","sequence":"additional","affiliation":[{"name":"International Joint Laboratory On Synthetic Biology and Biomass Biorefinery Biofuels Institute School of Emergency Management School of the Environment and Safety Engineering Jiangsu University  Zhenjiang P. R. China"},{"name":"Jiangsu Collaborative Innovation Center of Technology and Material of Water Treatment Suzhou University of Science and Technology  Suzhou P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9646-9556","authenticated-orcid":false,"given":"Daochen","family":"Zhu","sequence":"additional","affiliation":[{"name":"International Joint Laboratory On Synthetic Biology and Biomass Biorefinery Biofuels Institute School of Emergency Management School of the Environment and Safety Engineering Jiangsu University  Zhenjiang P. R. China"},{"name":"Jiangsu Collaborative Innovation Center of Technology and Material of Water Treatment Suzhou University of Science and Technology  Suzhou P. R. 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