Modular train-style nanorobots for targeted deep penetration and multi-directional collaborative treatment of colorectal cancer

Abstract

Colorectal cancer (CRC) remains a major global health challenge due to insufficient tumor penetration and immunosuppressive microenvironments. Herein, we propose a modular train-style nanorobot (TPP-Exo@LOX-Pd-Cu₇S₄) as a targeted synergistic therapeutic platform for CRC. The exosome “head” enables neutrophil-like tumor homing, while the Cu₇S₄ “tail” generates thermophoretic propulsion for deep tumor penetration. Under near-infrared region II (NIR-II) laser irradiation, the Pd-Cu₇S₄ Schottky heterojunction drives highly efficient catalytic cascades, disrupting redox homeostasis and inducing metabolic stress by converting O₂ to ·O₂⁻, H₂O₂ to ·OH, GSH to GSSG, NADH to NAD⁺, and lactate to pyruvate. The nanorobot directly targets mitochondria to reprogram tumor metabolism and trigger cuproptosis. Meanwhile, lactate oxidase (LOX), encapsulated within the engineered exosomes, depletes excess lactate to relieve immunosuppression and boost antitumor immunity. In CRC models, these nanorobots exhibit strong barrier penetration, precise targeting, and deep tumor infiltration, offering a multifunctional and metabolically disruptive therapeutic approach.