Inhaled engineered apoptotic neutrophil-derived nanovesicles enhance macrophage efferocytosis for attenuating lung inflammation

Acute respiratory distress syndrome (ARDS) is a life-threatening respiratory disorder characterized by uncontrolled lung inflammation and diffuse alveolar injury. The impaired macrophage efferocytosis represents a critical pathological mechanism obstructing inflammation resolution in ARDS. In this work, we developed an inhalable engineered apoptotic neutrophil-derived nanovesicle system (TA-Ce/NV) to remodel the lung inflammatory microenvironment by enhancing macrophage efferocytosis. By constructing a polyphenol-metal network protective layer on the surface of nanovesicles through the coordination of tannic acid and cerium ions, this strategy integrates dual functionalities: (1) enhancing nebulization stability of the nanovesicles to overcome limitations in nebulized delivery, and (2) synergizing the immunomodulatory effects of apoptotic vesicles with the reactive oxygen species-scavenging properties to activate macrophage continual efferocytosis. Following nebulized inhalation, TA-Ce/NV demonstrated prolonged retention in inflamed lungs and achieved deep lung deposition. TA-Ce/NV effectively alleviated lung inflammation and promoted tissue repair by activating endogenous repair mechanisms. Additionally, by surface adsorption of the anti-inflammatory cytokine IL-10, TA-Ce/NV served not only as a therapeutic entity but also as a delivery vehicle, providing an innovative therapeutic strategy for ARDS while establishing a novel inhaled delivery platform for pulmonary diseases.