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Here, this work presents an intravenously deliverable \u201cliving medicine\u201d that addresses these barriers through biomimetic cloaking, tumor\u2010penetrating guidance, and synthetic\u2010biology\u2010driven cytokine release.\n                    <jats:italic>Lactococcus lactis<\/jats:italic>\n                    is engineered to co\u2010secrete Flt3L and OX40L (FOLactis) and then camouflage with red\u2010blood\u2010cell membranes, producing long\u2010circulating mRBC@FOLactis. Conjugation of the iRGD peptide (iRGD\u2010mRBC@FOLactis) enables trans\u2010endothelial migration and deep (\u2265200\u00a0\u00b5m) interstitial penetration, yielding a fourfold increase in intratumorally bacterial accumulation versus unmodified FOLactis. In the orthotopic Lewis lung carcinoma (LLC) model, a single intravenous dose of iRGD\u2010mRBC@FOLactis combined with anti\u2010PD\u20101 antibody achieves complete tumor regression in 60% of mice, doubles median survival (\n                    <jats:italic>p<\/jats:italic>\n                    &lt; 0.001), and generates systemic tumor\u2010specific immune memory. Mechanistically, local Flt3L and OX40L secretion expands cross\u2010presenting dendritic cells (DCs), boosts CD8\u207a T\u2010cell priming, and converts immunologically \u201ccold\u201d tumors into inflamed, T\u2010cell\u2010rich lesions, thereby overcoming primary resistance to checkpoint blockade. This multifunctional probiotic platform establishes a generalizable strategy for systemic delivery of living therapeutics and offers a powerful adjunct to PD\u20101\/PD\u2010L1 blockade for NSCLC and other treatment\u2010resistant solid tumors.\n                  <\/jats:p>","DOI":"10.1002\/advs.202509604","type":"journal-article","created":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T13:20:56Z","timestamp":1759497656000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Intravenous iRGD\u2010Guided, RBC\u2010Membrane Camouflaged\n                    <i>Lactococcus Lactis<\/i>\n                    Remodels Cold NSCLC and Enhances PD\u20101 Blockade"],"prefix":"10.1002","volume":"12","author":[{"given":"Chen","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Oncology Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School Nanjing University  Nanjing 210008 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