# Engineered Extracellular Vesicles Driven by Erythrocytes Ameliorate Bacterial Sepsis by Iron Recycling, Toxin Clearing and Inflammation Regulation

## TL;DR

Engineered extracellular vesicles driven by red blood cells help treat sepsis by capturing iron, neutralizing toxins, and reducing inflammation.

## Contribution

A multifunctional sepsis treatment using erythrocyte-driven, engineered apoptotic extracellular vesicles is developed.

## Key findings

- Engineered apoEVs bind iron-containing proteins and neutralize α-toxin via membrane receptors.
- Incorporation of anti-inflammatory microRNA-146a enhances inflammation regulation.
- Erythrocyte-driven apoEVs show high toxin and iron capture capacity, protecting against sepsis.

## Abstract

Sepsis poses a significant challenge in clinical management. Effective strategies targeting iron restriction, toxin neutralization, and inflammation regulation are crucial in combating sepsis. However, a comprehensive approach simultaneously targeting these multiple processes has not been established. Here, an engineered apoptotic extracellular vesicles (apoEVs) derived from macrophages is developed and their potential as multifunctional agents for sepsis treatment is investigated. The extensive macrophage apoptosis in a Staphylococcus aureus‐induced sepsis model is discovered, unexpectedly revealing a protective role for the host. Mechanistically, the protective effects are mediated by apoptotic macrophage‐released apoEVs, which bound iron‐containing proteins and neutralized α‐toxin through interaction with membrane receptors (transferrin receptor and A disintegrin and metalloprotease 10). To further enhance therapeutic efficiency, apoEVs are engineered by incorporating mesoporous silica nanoparticles preloaded with anti‐inflammatory agents (microRNA‐146a). These engineered apoEVs can capture iron and neutralize α‐toxin with their natural membrane while also regulating inflammation by releasing microRNA‐146a in phagocytes. Moreover, to exploit the microcosmic movement and rotation capabilities, erythrocytes are utilized to drive the engineered apoEVs. The erythrocytes‐driven engineered apoEVs demonstrate a high capacity for toxin and iron capture, ultimately providing protection against sepsis associated with high iron‐loaded conditions. The findings establish a multifunctional agent that combines natural and engineered antibacterial strategies.

Here, apoptotic extracellular vesicles (apoEVs) are found to bind iron‐containing proteins and neutralize α‐toxin by membrane receptors. The apoEVs are further engineered by incorporating material loaded with anti‐inflammatory microRNA‐146a and are connected to erythrocytes to harness their movement and rotation abilities in circulation. The engineered erythrocytes‐driven apoEVs show high capacity to capture toxin and iron, regulate inflammation and protect against sepsis.