Inflammatory diseases such as acute lung injury and ischaemic tissue injury are caused by the adhesion of a type of white blood cell—polymorphonuclear neutrophils—to the lining of the circulatory system or vascular endothelium and unchecked neutrophil transmigration^1,2. Nanoparticle-mediated targeting of activated neutrophils on vascular endothelial cells at the site of injury may be a useful means of directly inactivating neutrophil transmigration and hence mitigating vascular inflammation³. Here, we report a method employing drug-loaded albumin nanoparticles, which efficiently deliver drugs into neutrophils adherent to the surface of the inflamed endothelium. Using intravital microscopy of tumour necrosis factor-α-challenged mouse cremaster post-capillary venules, we demonstrate that fluorescently tagged albumin nanoparticles are largely internalized by neutrophils adherent to the activated endothelium via cell surface Fcɣ receptors. Administration of albumin nanoparticles loaded with the spleen tyrosine kinase inhibitor, piceatannol, which blocks ‘outside-in’ β2 integrin signalling in leukocytes, detached the adherent neutrophils and elicited their release into the circulation. Thus, internalization of drug-loaded albumin nanoparticles into neutrophils inactivates the pro-inflammatory function of activated neutrophils, thereby offering a promising approach for treating inflammatory diseases resulting from inappropriate neutrophil sequestration and activation.

Sepsis is a life‐threatening disease resulted from a dysregulated host immune response to bacterial infections, continuing to cause high morbidity and mortality worldwide. Despite discoveries of many potential therapeutic targets, effective treatments of sepsis are lacking. Here, a strategy is reported to target infectious microenvironments (IMEs) via bioresponsive nanoparticles that simultaneously eliminate bacteria and alleviate the host inflammation response, thus managing sepsis in mice. The nanoparticle is made of copolymers sensitive to pH and bacterial enzymes to self‐assemble into a micelle loaded with both an antibiotic (ciprofloxacin) and an anti‐inflammatory agent ((2‐[(aminocarbonyl)amino]‐5‐(4‐fluorophenyl)‐3‐thiophenecarboxamide). In addition, the nanoparticle is conjugated with intercellular adhesion molecule‐1 antibodies to target IMEs. Nanoparticle targeting to IMEs and local cues as triggers to deliver therapeutics in on‐demand manners is demonstrated using an acute lung bacterial infection mouse model. In the sepsis mouse model induced by peritonitis at a lethal dose of bacterial invasion, it is shown that concurrently targeting pathogens and excessive inflammation pathways is valuable to manage the sepsis. The study illustrates not only the development of a new delivery system but also the mechanism‐based therapy of nanomedicine for infectious diseases.