X-ray-driven nanomotor with enhanced penetration and retention for carbon monoxide-amplified radioimmunotherapy of advanced colorectal cancer

TL;DR

A new X-ray-activated nanomotor improves cancer treatment by enhancing drug delivery and immune response in advanced colorectal cancer.

Contribution

Development of an X-ray-driven nanomotor that combines CO generation and immune activation for enhanced radioimmunotherapy.

Findings

X-ray irradiation of GM-R848 generates CO bubbles, improving drug penetration and retention in tumor tissues.

CO amplifies DNA damage and R848 boosts anti-tumor immunity, leading to 95.3% tumor growth inhibition in an advanced CRC model.

Abstract

Most advanced colorectal cancer (CRC) with peritoneal metastasis have been managed by radiotherapy and following localized perfusion of therapeutic agents. However, the efficacy of intraperitoneal treatment remains limited by poor drug penetration, inadequate retention within tumor tissues, and a complex tumor microenvironment. Here we report the development of an X-ray-activated nanomotor, GM-R848, comprising an iron carbonyl (FeCO) prodrug framework encapsulating the TLR7 agonist resiquimod (R848), designed for efficient tumor cell elimination and immune activation. Upon X-ray irradiation, rapid decomposition of the FeCO framework generates carbon monoxide (CO) bubbles, propelling enhanced penetration and retention of the nanomotors within colorectal tumor tissues. Following internalization, CO amplifies DNA damage to sensitize tumor cells to radiotherapy, thereby inducing immunogenic cell death. Concurrently, the sequential release of R848 stimulates robust immune activation, synergistically enhancing anti-tumor immunity within the peritoneal cavity. This integrated radio-gas-immunotherapy strategy achieved a 95.3 % tumor growth inhibition rate in an advanced CRC model while mitigating adverse effects associated with radiotherapy and immunotherapy. These findings create a framework for X-ray-driven nanorobots in precision oncology, offering a promising approach for the targeted management of advanced cancers.

Upon X-ray irradiation, GM-R848 rapidly generates CO bubbles, potentiating enhanced penetration and retention within colorectal tumor tissues. CO potentiates radiosensitization by amplifying DNA damage, while concurrently released R848 activates robust anti-tumor immunity, synergistically suppressing advanced CRC progression.Image 1

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