Salmonella biomimetic Janus nanorobots reinvigorate colorectal cancer radio-immunotherapy by glycolysis inhibition and cGAS-STING activation.

Abstract

Colorectal cancer remains a major therapeutic challenge due to the immunosuppressive tumor microenvironment and physical barriers that limit drug delivery. Here, we present near-infrared (NIR)-II laser-actuated biomimetic nanorobots (Au-mSiO₂@MnCO@SM) designed to overcome these hurdles and potentiate radio-immunotherapy. These nanorobots combine a self-thermophoretic Janus core for active propulsion, a tumor-microenvironment-responsive carbon monoxide (CO) release module for glycolysis suppression and radiosensitization, and a Salmonella membrane coating for enhanced mucus penetration and tumor targeting. Upon reaching tumors, the platform disrupts mitochondrial metabolism, amplifies cytosolic dsDNA via radiation and CO therapy, and releases Mn²⁺ to synergistically activate the cGAS-STING pathway. This ignites a robust antitumor immune response, complemented by immunogenic cell death. Both in vitro and in vivo experiments demonstrate effective tumor targeting, deep penetration, and significant tumor growth suppression. This work provides a promising and potent strategy for advanced colorectal cancer treatment. STATEMENT OF SIGNIFICANCE: The forbidden biological barriers seriously restrict the delivery efficacy of nanomaterials for treating various major diseases. Herein, we propose orally administrated biomimetic nanorobots with prolonged intestinal retention, enhanced mucus barrier penetration, and tumor-targeting and accumulation characteristics to treat colorectal cancer. By leveraging nanorobot motility, Salmonella-inspired targeting, CO gas-enabled metabolic modulation, and Mn²⁺-driven cGAS-STING activation, such biomimetic nanorobots can provoke robust radio-immunological responses, which should open a new horizon in the design of nanorobots for radio-immunotherapy.