A near-infrared light-triggered nano-domino system for efficient biofilm eradication: Activation of dispersing and killing functions by generating nitric oxide and peroxynitrite via cascade reactions

One of the serious threats to global public health is the bacterial biofilm, which results in numerous persistent and recurrent infections. Herein, we proposed a near-infrared (NIR) light-triggered "nano-domino" system with "dispersing and killing" functionality for biofilm eradication. The nanoplatform was fabricated by the self-assembly of chitosan conjugated with L-arginine (L-Arg, a natural nitric oxide (NO) donor) and indocyanine green (ICG, a phototherapy agent). Using an NIR irradiation "trigger", a series of reactive oxygen species (ROS) including singlet oxygen (1O2), hydrogen peroxide (H2O2), and superoxide anions (·O2-), as well as heat were generated from ICG aggregates. Subsequently, 1O2 and H2O2 catalyzed L-Arg to produce NO, which dispersed the biofilm and reacted with ·O2- to form peroxynitrite to kill bacteria with ROS collaboratively. Meanwhile, the generated heat increased the permeability of bacterial membranes, aggravating the damage to biofilm bacteria. The experiments on biofilm eradication demonstrated that this "nano-domino" system was capable to eradicate over 99.99% of biofilms formed by Methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa under 5-min NIR irradiation. Notably, these integrated benefits allowed the system to promote the healing of MRSA biofilm-infected wounds in vivo with negligible toxicity. Overall, this reported NIR-triggered "nano-domino" system holds great promise for addressing the difficulties associated with bacterial biofilm eradication. STATEMENT OF SIGNIFICANCE: Novel agents for biofilm eradication are urgently needed due to the alarming rise in antimicrobial resistance to conventional antibiotics and the critical shortage of new drugs. In this study, we created a nano-domino system that uses near-infrared (NIR) light as a trigger to eradicate mature biofilms. In response to a short-term NIR irradiation, the proposed nanoplatform could generate nitric oxide and peroxynitrite to disperse the biofilm and kill the bacteria inside, respectively, leading to efficient eradication of Methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa biofilms with minimal cytotoxicity. The findings, therefore, indicate that this nanoplatform with enhanced antibiofilm performance might provide a reliable and promising solution to biofilm-related problems.