Programmed degradable core-shell nanoparticles eradicate mature biofilm via precise in-situ phototherapy

Combating bacterial biofilm poses a significant challenge because of the dense extracellular polymeric substance (EPS) barrier and inherent drug tolerance. Herein, the designed core-shell nanoparticles (DA 3 -NPs) that eradicate biofilm by precise in-situ phototherapy are reported. DA 3 -NPs are self-assembled using thermosensitive azo-polymers (AP 3 ) to encapsulate GSH-degradable phototherapeutic polymers (DBP) via charge interaction. Notably, D -aminoalanine grafted onto the AP 3 serves as a critical component, providing an electroneutral shell and bacterial peptidoglycan targeting ability to the DA 3 -NPs. Consequently, DA 3 -NPs effectively penetrate EPS up to a depth of 60 µm and precisely target the bacteria within the biofilms. Upon exposure to laser irradiation and the GSH microenvironment, DA 3 -NPs undergo sequential responses involving shell detachment and core disintegration. These processes facilitate point-to-point bacterial killing through the in-situ generations of ROS, carbon radicals and heat damage to the internal bacteria. Compared to non-targeted nanoparticles, DA 3 -NPs exhibit a 61-fold increase in biofilm removal efficiency. This study thus presents a precise in-situ phototherapy strategy for nonantibiotic treatment of biofilm infections.