Targeting Bacterial Persisters via Reactive Oxygen Species‐Generating Hydrogel Microspheres

Abstract The presence of bacterial persisters is a key factor contributing to chronic infection. However, no effective treatment methods are currently available. Thus, a platform is developed, called reactive oxygen species (ROS) bomb, based on microenvironment‐adaptive hydrogel microspheres, to oxidize the cell membranes of persisters in chronic periprosthetic joint infection (PJI). Fenton reagent hydroxy iron oxide (FeOOH) and a glucose oxidase (GOx)/calcium phosphate (CaP) acid‐responsive shell are sequentially induced on the surface of mesoporous polydopamine (PDA) nanoparticles by the PDA‐mediated ion precipitation and interfacial adhesion, followed by the coloaded with glucose into microfluidic hyaluronic acid hydrogel microspheres. Hydroxyl radicals are explosively generated through GOx‐mediated glucose oxidase, H 2 O 2 production, and its Fenton‐like reactions with FeOOH, which also benefit from the weakly acidic microenvironment around persisters, result in the destruction of bacterial cell membrane, and subsequent overflow of cellular contents such as dsDNA, proteins, and K + . The bactericidal rates of methicillin‐resistant Staphylococcus aureus and Staphylococcus epidermidis persisters are up to 99.14% and 98.96%, and the bacterial loads in lesion location are significantly decreased after ROS bombs treated, effectively alleviated the inflammation and bone resorption damage. This work provides a new strategy toward persisters clearance and shows great application potential in other chronic infection‐related diseases.