Lipase-Responsive Nitric Oxide Releasing Degradable Nanoparticles Targeting Bacterial Biofilm

Nitric oxide (NO) has shown promising potential for biofilm dispersal, but small NONOate (diazeniumdiolate) molecules have rapid diffusion, short half-life, and uncontrolled release, which limit their therapeutic applications. Grafting NO donors onto a polymer backbone reduces uncontrolled release and toxicity. However, previous works generally have uncontrolled NO release in water and are not responsive to the bacterial microenvironment. Herein, biodegradable block copolymers of polyethylene glycol (PEG)-block-polycaprolactone (PCL) derivatives as scaffolds were employed. The PCL block was diazeniumdiolate (NONOate)-functionalized, and the PEG-to-PCL ratio was varied. Two series of lipase-responsive NO-releasing biodegradable nanoparticles were made from (a) anionic and (b) mixed-charge NONOate species. The mixed-charge series with PEG produces a stable core–shell morphology that does not release NO by itself but can be triggered to release NO only when lipase is present. The lead nanoparticle exhibits superior efficacy in dispersing biofilms of both Gram-negative and Gram-positive bacteria.