“Thermal bubbles”: Photothermally triggered by a carbon monoxide nanocontainer for antibiosis and immune modulation therapy

Carbon monoxide (CO) has multi-biofunctions, including antibiosis and immunoregulation, promising great therapeutic potential. However, poor controllability of releasing, unbalanced dose for antibiosis and cytocompatibility, and unexplored antibacterial mechanism, limit its practical application. To address these issues, a photo-responsive COT nanocontainer is designed on Ti by loading thermosensitive CO donors in PDA-modified TiO₂ nanotubes. The nanocontainer shows outstanding photothermal properties, so as to break the Mn-CO bonds of CO donors under near-infrared (NIR) irradiation, generating thermal CO bubbles on-demand by regulating NIR power, and thus realizing different therapy modes. At antibacterial mode of COT with high-power NIR irradiation (e.g., 0.7 W cm⁻²), abundant hyperthermal CO bubbles from COT kill bacteria efficiently by inducing bacterial ferroptosis, which is demonstrated by hallmarks of overloaded Fe ions, lipid peroxidation, glutathione depletion, etc. At immunoregulation mode with low-power NIR irradiation (e.g., 0.3 W cm⁻²), mild thermal CO bubbles help macrophages to polarize into anti-inflammatory M2 phenotype, and they combine with cytokines from M2 macrophages to promote fibroblast response. These dual therapy modes of COT are verified to kill bacteria, modulate immunoreaction, and accelerate tissue repair in infected models. This study provides a controllable therapy strategy for using CO in treating infection and improving tissue regeneration.