Engineered mitochondrial ROS scavenger nanocomplex to enhance lung biodistribution and reduce inflammation for the treatment of ARDS

Abstract

Acute respiratory distress syndrome (ARDS) continues to be a life-threatening challenge, especially for patients in intensive care units (ICUs). Despite extensive research, cost-effective treatments remains elusive, primarily due to the difficulties in delivering adequate medications to damaged tissues and managing lung inflammation. This study presents a novel approach in which mitochondrial and lung-targeting liposomes loaded with ROS scavengers (LMR) were constructed through fusion. Briefly, mitochondria were extracted from human AC16 cardiac muscle cells using a specific commercial kit. Characterization involved techniques such as TEM imaging, zeta potential analysis, and SDS-PAGE. PCR and qRT-PCR were used to measure gene expression, while ROS levels were detected using a microplate reader. The lung-targeted liposomes ensured prolonged retention, thereby facilitating their immunoregulatory functions. By targeting mitochondrial damage and oxidative stress, LMR showed improved ATP production and reduced LPS-induced ROS stress in macrophages. Treatment with LMR not only enhanced mitochondrial integrity but also shifted macrophages towards an anti-inflammatory state, evidenced by reduced expression of TNF-α, IL-1β, CD86, and IL-6 and increased production of the anti-inflammatory cytokine CD206. This reduction in inflammation and oxidative stress led to improved therapeutic outcomes in a mouse model of ARDS. Overall, this hybrid nanoplatform offers a versatile strategy for drug delivery by integrating biomaterials and therapeutic agents through the fusion of mitochondria with liposomes, thereby enhancing lung biodistribution and amplifying the anti-inflammatory response in ARDS treatment.