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

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(ε-caprolactone) (PECL-ad) amphiphilic copolymers are linked with cd-PTTA via host–guest complexation and simultaneously self-assembled into [email protected] micelles. The digestion of poly(ε-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 [email protected] 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.