Pseudomonas aeruginosa-targeted mesoporous gold nanorod nanogenerator: NIR laser-triggered alkyl radical generation for enhanced bacterial wound treatment

Currently, <i>Pseudomonas aeruginosa</i> (<i>P. aeruginosa</i>) infections pose a significant threat to public health, owing to the high morbidity, mortality and antibiotic resistance. Alkyl radical (AR)-based photodynamic therapy exhibits great potential in antibacterial applications due to its oxygen-independent advantage. Nevertheless, targeted delivery systems capable of precisely controlling AR release at bacterial infectious foci are still lacking. In the present work, a mesoporous gold nanorod (mGNR)-based multifunctional nanogenerator with <i>P. aeruginosa</i>-targeting and near infrared (NIR) laser-controlled AR release properties was fabricated for enhanced bacterial wound treatment. Herein, mGNR with mild-photothermal therapeutic (MPTT) effect was firstly synthesized and used as a carrier for effective loading of an AR initiator 2, 2'-azobis[2-(2-imidazolin-2-yl)propane]-dihydrochloride (AIPH). Then, cysteamine and polymer of HOOC-PEG₅₀₀₀-Mal were added in sequence to functionalize the nanosystem, obtaining nanogenerator of mGNR@AIPH@PEG-Mal. Due to the specific maleimide (Mal) and Type IV Pilus (T4P) reaction, mGNR@AIPH@PEG-Mal displayed high binding efficiency on <i>P. aeruginosa</i>. Upon NIR laser irradiation, mGNR@AIPH@PEG-Mal triggered AIPH cleavage to generate substantial amount of AR, which enabled high-efficient inhibition on <i>P. aeruginosa</i> and biofilms <i>via</i> the synergistic MPTT/AR antibacterial effect. Moreover, mGNR@AIPH@PEG-Mal exhibited excellent antibacterial and wound healing effect on <i>P. aeruginosa</i> infectious rats' wounds. In-depth mechanism study revealed that the synergistic MPTT/AR therapeutic effect of mGNR@AIPH@PEG-Mal induced <i>P. aeruginosa</i> death by breaking bacterial membrane, triggering ROS boost, GSH depletion and DNA damage, as well as promoted wound healing by repolarizing M2-type macrophages and upregulating CD 31 and α-SMA expressions.