Staphylococcus aureus bacteremia is one of the most serious bacterial infections worldwide. Most complications of S. aureus bacteremia arise because the pathogen can survive inside host phagocytes, especially macrophages, which makes elimination of intracellular S. aureus key to clinical success. Unfortunately, most antibiotics have poor cellular penetration capacity, which necessitates intracellular delivery of antibiotics. We herein use nanoparticle coated with membrane of extracellular vesicle secreted by S. aureus (i.e., NP@EV) as active-targeting antibiotic carrier, with counterparts coated with PEGylated lipid bilayer (i.e., NP@Lipo; PEG = poly(ethylene glycol)) or with membrane of outer membrane vesicle secreted by Escherichia coli (i.e., NP@OMV) included as controls. NP@EV is internalized at higher efficiency by S. aureus-infected macrophage than by nai ̈ve counterpart, whereas NP@Lipo and NP@OMV are not; instead, NP@OMV, but neither NP@EV nor NP@Lipo, is internalized at higher efficiency by E. coli-infected macrophage than by nai ̈ve counterpart. Moreover, when injected intravenously into mouse models, NP@EV, but neither NP@OMV nor NP@Lipo, exhibits significantly higher accumulations within four major organs (kidney, lung, spleen, and heart) bearing metastatic S. aureus infections than within healthy counterparts. These observations suggest that EV membrane coating of NP@EV endows the particle with active targeting capacity both in vitro and in vivo. As a result, when preloaded with antibiotics and intravenously administered to alleviate metastatic infection in S. aureus bacteremia-bearing mouse model, NP@EV confers its cargoes with strikingly improved efficacy; in doing so, NP@EV is significantly more efficient than both NP@Lipo and NP@OMV in kidney and lungwhich bear the highest metastatic bacterial burden and represent most common sites for S. aureus infection, respectively. Such an active-targeting delivery platform may have implications in promoting clinical success on intracellular pathogen-associated complications.

Narrow-spectrum antimicrobials specifically eradicate the target pathogens but suffer from significantly lagging development. Photodynamic therapy eliminates cells with reactive oxygen species (ROS) generated upon light irradiation but is intrinsically a wide-spectrum modality. We herein converted photodynamic therapy into a narrow-spectrum modality by taking advantage of a previously unnoticed physics recognition pathway. We found that negatively charged nanospheres undergo selective entropy gain-driven adsorption onto spherical bacteria, but not onto rod-like bacteria. This bacterial morphology-targeting selectivity, combined with the extremely limited effective radii of action of ROS, enabled photodynamic nanospheres to kill >99% of inoculated spherical bacteria upon light irradiation and <1% of rod-like bacteria under comparable conditions, indicative of narrow-spectrum activity against spherical bacteria. This work unveils the bacterial morphology selectivity in the adsorption of negatively charged nanospheres and suggests a new approach for treating infections characterized by overthriving spherical bacteria in niches naturally dominated by rod-like bacteria.