Targeted lactate depletion via gluconeogenesis by engineered hepatocyte-based micronanorobots for radiosensitization and immune activation.

Abstract

Radiotherapy is often limited by tumor-intrinsic DNA repair and an immunosuppressive microenvironment, both of which are reinforced by lactate accumulation. Here, we develop a CXCR4-engineered enucleated hepatocyte cytoplast platform decorated with Au-Pt Janus nanorobots (AP/LCCXCR4) to deplete intratumoral lactate and amplify radiation-induced oxidative stress. The hepatocyte cytoplasts home to tumors and consume lactate through gluconeogenesis, reducing repair-associated protein lactylation and impairing MRE11-RAD50-NBS1 (MRN) co-fractionation and chromatin recruitment, thereby impairing double-strand break repair. In parallel, the Au-Pt nanorobots enhance reactive oxygen species generation under acidic tumor conditions, increasing radiation damage. In radioresistant colorectal cancer models and a metastatic cervical cancer model, AP/LCCXCR4 combined with radiotherapy sustains DNA damage, promotes immunogenic cell death, reduces immunosuppressive myeloid and regulatory T (Treg) cell populations, enhances dendritic cell maturation and CD8+ T cell activation, and improves tumor control and survival.