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

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.