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Biological strategies capable of enhancing nanomedicine performance through modulation of host-response pathways, rather than additional nanoparticle engineering, remain largely unexplored. Herein, we investigated whether a microbial levan produced by\n                    <jats:italic>Weissella paramesenteroides<\/jats:italic>\n                    could potentiate the therapeutic activity of a PEGylated \u03b2-cyclodextrin-capped benzimidazole\u2013curcumin nanocomplex (BMPE\u2013Cur) in an Ehrlich ascites carcinoma (EAC)-induced hepatic tumor model. Pharmacokinetic, biochemical, histopathological, angiogenic, immunological, molecular, and computational analyses were performed to evaluate therapeutic efficacy and explore underlying mechanisms. The co-administration of levan increased hepatic BMPE accumulation by 2.3-fold and significantly enhanced the therapeutic efficacy of BMPE\u2013Cur, improving survival to 95.45% compared with 60.66% mortality in untreated tumor-bearing mice. Combination therapy produced 86% inhibition of angiogenesis, markedly suppressed tumor-associated biomarkers, oxidative stress, inflammatory mediators, and immunosuppressive cell populations, and restored hepatic function. These effects were accompanied by reduced expression of components of the TLR2\/\n                    <jats:italic>MyD88<\/jats:italic>\n                    \/\n                    <jats:italic>NF-\u03baB<\/jats:italic>\n                    pathway, including an 80.05% reduction in\n                    <jats:italic>MyD88<\/jats:italic>\n                    and a 78.93% reduction in\n                    <jats:italic>NF-\u03baB<\/jats:italic>\n                    , together with 6.59-fold and 7.45-fold increases in\n                    <jats:italic>FXR<\/jats:italic>\n                    and\n                    <jats:italic>FGF15<\/jats:italic>\n                    expression, respectively. Molecular docking supported potential interactions of BMPE, curcumin, and levan-derived structural motifs with TLR2, while isobolographic analysis demonstrated predominantly synergistic interactions across multiple biological endpoints. These findings support the potential of microbial levan as a promising biological potentiator of nanotherapeutic efficacy, with concurrent enhancement of hepatic nanocomplex retention and coordinated immunometabolic remodeling. More broadly, microbial exopolysaccharides may represent a promising class of host-response modulators, supporting a therapeutic paradigm in which optimizing the biological environment may complement conventional nanocarrier engineering to improve the performance of cancer nanomedicine.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-64576-8","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T02:33:23Z","timestamp":1786502003000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Microbial levan potentiates hepatic retention and antitumor activity of a PEGylated benzimidazole\u2013curcumin nanocomplex through TLR2\u2013FXR\/FGF15-associated immunometabolic remodeling in experimental liver cancer"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8403-1143","authenticated-orcid":false,"given":"Heba","family":"Shawky","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7176-4687","authenticated-orcid":false,"given":"Noha E.","family":"Ibrahim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9881-8382","authenticated-orcid":false,"given":"Mai N.","family":"Amer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9219-5436","authenticated-orcid":false,"given":"Aisha A. 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