Light-triggerable and pH/lipase-responsive release of antibiotics and β-lactamase inhibitors from host-guest self-assembled micelles to combat biofilms and resistant bacteria

Abstract Major challenges remain in combat with the inevitable rise of intrinsic resistance to antibiotics and biofilm formation. Herein, we explore host–guest self-assembled micelles for light-triggered and stimuli-responsive release of antibiotics and β-lactamase inhibitors to combat biofilms derived from methicillin-resistant Staphylococcus aureus (MRSA). β-Cyclodextrin-capped phenylboronic acid-tetraphenylethylene (PBA-TPE) conjugates are coupled with ampicillin (Amp) via reactive oxygen species (ROS)-cleavable thioketal linkers to obtain cd-PTTA prodrug. Adamantane-capped poly(ethylene glycol)-poly(e-caprolactone) (PECL-ad) amphiphilic copolymers are linked with cd-PTTA via host–guest complexation and simultaneously self-assembled into PECL@PTTA micelles. The digestion of poly(e-caprolactone) segments by bacterial lipase destructs micelles and the aggregation-induced emission feature of cd-PTTA leads to ROS generation after light illumination. The produced ROS destroys biofilms and breaks thioketal linkers to release Amp antibiotics, while the pH-responsive removal of β-cyclodextrin activates the PBA β-lactamase inhibitors, affording synergistic actions on MRSA. The light illumination and intrinsic signals of acidic pH and lipase display interactive promotions of Amp release, micelle destabilization, and β-lactamase inhibition. Compared to those of cd-PTTA, the PECL@PTTA micelle treatment under light exposure shows sustained growth inhibition of planktonic MSRA, 2-fold higher elimination rate of biofilms, and 28-fold lower number of live MRSA embedded in biofilms. In an MRSA subcutaneous infection model, the micelle treatment with light exposure could eradicate bacteria and a complete wound closure was observed with normal re-epithelialization and skin morphology. Thus this strategy enables synchronous release of antibiotics and activation of β-lactamase inhibitors for photodynamic destruction of biofilms and restoration of the antibiotic activity to resistant bacteria embedded.