Photoactivatable Nitric Oxide-Releasing Gold Nanocages for Enhanced Hyperthermia Treatment of Biofilm-Associated Infections

With the increasing clinical use of invasive medical devices, various healthcare-associated infections (HAIs) caused by bacterial biofilm colonization of biomedical devices have posed serious threats to patients. The formation of biofilms makes it much more difficult and costly to treat infections. Here, we report a nitric oxide (NO)-releasing gold nanocage (AuNC@NO) that is stimulated by near-infrared (NIR) irradiation to deliver NO and generate hyperthermia for biofilm elimination. AuNC@NO was prepared by immobilizing a temperature-responsive NO donor onto gold nanocages (AuNCs) through thiol-gold interactions. AuNC@NO possesses stable and excellent photothermal conversion efficiency, as well as the characteristics of slow NO release at physiological temperature and on-demand quick NO release under NIR irradiation. Based on these features, AuNC@NO exhibits enhanced in vitro bactericidal and antibiofilm efficacy compared with AuNCs, which could achieve 4 orders of magnitude bacterial reduction and 85.4% biofilm elimination under NIR irradiation. In addition, we constructed an implant biofilm infection model and a subcutaneous biofilm infection model to evaluate the anti-infective effect of AuNC@NO. The in vivo results indicated that after 5 min of 0.5 W cm-2 NIR irradiation, NO release from AuNC@NO was significantly accelerated, which induced the dispersal of methicillin-resistant Staphylococcus aureus (MRSA) biofilms and synergized with photothermal therapy (PTT) to kill planktonic MRSA that had lost its biofilm protection. Meanwhile, the surrounding tissues showed little damage because of controlled photothermal temperature and toxicity. In view of the above-mentioned results, the AuNC@NO nanocomposite developed in this work reveals potential application prospects as a useful antibiofilm agent in the field of biofilm-associated infection treatment.