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To address these limitations, we developed a drug\u2010encapsulated lipid nanoparticle (LNP) system to reprogram tumor metabolism and reverse acquired immune tolerance. This LNP encapsulates the cytotoxic agent monomethyl auristatin E (MA) and the immunomodulator metformin (Met), followed by conjugated to a human receptor tyrosine kinase\u2010like orphan receptor 1 antibody (ROR1 Ab) via an acid\u2010labile linker. ROR1 Ab\u2010mediated active targeting enables precise tumor localization through NIR\u2010II fluorescence imaging, and enhances chemotherapeutic efficacy while minimizing off\u2010target toxicity. Critically, metformin incorporated into the lipid formulation inhibits both membrane and cytoplasmic PD\u2010L1 expression and reduces TGF\u2010\u03b21 levels by suppressing mitochondrial oxidative phosphorylation (OXPHOS), thereby restoring T lymphocyte activity and amplifying the immune response. This work demonstrates a novel approach to enhance TNBC treatment through targeted modulation of tumor metabolism and immune activation.<\/jats:p>","DOI":"10.1002\/advs.202518468","type":"journal-article","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T14:47:19Z","timestamp":1769525239000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Universal Antibody\u2010Engineered Lipid Nanoparticles Potentiate Chemo\u2010Immunotherapy Against Triple\u2010Negative Breast Cancer by Reprogramming Tumor Cell Metabolism"],"prefix":"10.1002","volume":"13","author":[{"given":"Yeneng","family":"Dai","sequence":"first","affiliation":[{"name":"Cancer Centre Institute of Translational Medicine Faculty of Health Sciences University of Macau  Taipa Macau SAR China"},{"name":"MoE Frontiers Science Center for Precision Oncology University of Macau  Taipa Macau SAR 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