Dual-activated nanomotors as a theranostic platform for photoacoustic imaging-guided combination cancer therapy

High concentrations of nitric oxide (NO) can induce tumor cell death. However, its limited biological half-life and off-target effects restrict its clinical application. Herein, a dual-triggered NO-releasing nanomotor with an asymmetric bowl structure was designed, which is composed of tightly assembled gold nanoparticles and loaded with the NO donor N,N'-di-sec-butyl-N,N'-di-nitroso-1,4-phenylenediamine (BNN6). The special bowl-like structure provided a self-thermophoretic propulsion for nanomotors under near-infrared (NIR) light irradiation, enhancing their diffusion in tumor tissue. Furthermore, while achieving NO release, photoacoustic (PA) imaging-guided photothermal therapy (PTT) has also been realized. Additionally, with the assistance of ultrasound (US) perturbation, the nanomotor synergizes with NIR light to further promote the penetration capacity of the nanomotor in the dense tumor tissue. In addition, the special structure enhances the ultrasonic cavitation effect, which induces reactive oxygen species (ROS) production, thereby resulting in cell death by oxidative stress and achieving sonodynamic therapy (SDT). Notably, ROS and NO results in the formation of reactive nitrogen species (RNS) with higher toxicity, which further enhances antitumor efficacy. This strategy integrates gas therapy, PTT, and SDT via NIR/US dual-activated nanomotors, combining RNS with local hyperthermia for enhanced tumor treatment, offers an inspiration for developing novel cancer therapeutics.