Universal Antibody‐Engineered Lipid Nanoparticles Potentiate Chemo‐Immunotherapy Against Triple‐Negative Breast Cancer by Reprogramming Tumor Cell Metabolism

ABSTRACT Despite the promise of combining chemotherapy and immunotherapy for triple‐negative breast cancer (TNBC), challenges remain due to targeting deficiencies and accelerated T cell exhaustion within the immunosuppressive tumor microenvironment (TME). To address these limitations, we developed a drug‐encapsulated 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‐like orphan receptor 1 antibody (ROR1 Ab) via an acid‐labile linker. ROR1 Ab‐mediated active targeting enables precise tumor localization through NIR‐II fluorescence imaging, and enhances chemotherapeutic efficacy while minimizing off‐target toxicity. Critically, metformin incorporated into the lipid formulation inhibits both membrane and cytoplasmic PD‐L1 expression and reduces TGF‐β1 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.