A bioinspired hierarchical nanoplatform targeting and responding to intracellular pathogens to eradicate parasitic infections

Intracellular bacteria-mediated antibiotic tolerance, which acts as a "Trojan horse," plays a critical and underappreciated role in chronic and recurrent infections. Failure of conventional antibiotic therapy is often encountered because infected cells prevent drug permeation or the drug concentration is too low at the site of resident bacteria. New paradigms are therefore urgently needed for intracellular anti-infective therapy. Here, a novel therapeutic was developed for targeted delivery of antibiotics into bacteria-infected macrophages to improve drug accumulation in intracellular niches and bactericidal activity of antibiotics against intracellular pathogens. This hierarchical nanoplatform includes a glycocalyx-mimicking shell that enables rapid uptake by macrophages. Subsequently, the targeting moieties are activated in response to the bacteria, and the release of entrapped antibiotics is triggered by bacteria and bacteria-secreted enzymes. The self-immolative drug delivery nanoplatform eliminates intracellular pathogenic bacteria residing in macrophages more efficiently compared to drugs alone. The in vivo dynamically monitored nanosystem also efficiently inhibited the growth of intracellular Staphylococcus aureus in infected muscles of mice with negligible systemic toxicity. The novel dual-targeting design of an all-in-one therapeutic platform can be used as an alternative strategy to reanimate antibiotic therapy against multifarious intracellular bacterial infections.