Fucoidan-based smart micelles enable P-selectin-targeted and ROS-responsive delivery of mitochonic acid 5 for mitochondrial functional improvement in acute lung injury

Targeting mitochondrial dysfunction in inflamed lung vessels addresses a key challenge in acute lung injury treatment, where current therapies lack precision and efficacy. • We develop smart nanoparticles that actively seek out injured blood vessels and release medicine only where oxidative stress is high, enabling enhanced mitochondrial repair. • This strategy markedly improves lung function and survival in mice with acute lung injury, demonstrating a promising approach for treating severe pulmonary inflammation. Acute lung injury (ALI) is a life-threatening condition with complex pathogenesis. Mitochondrial dysfunction in pulmonary vascular endothelial cells serves as a central hub, driving oxidative stress, inflammation, and barrier disruption. Existing treatments are limited by poor targeting and insufficient efficacy. To address this, we engineered a novel dual-targeting nanoplatform, P-selectin-directed and ROS-responsive fucoidan micelles loaded with the mitochondrial modulator Mitochonic Acid 5 (Fuc-TP@MA-5). Here we show that this system actively homes to inflamed lung endothelium via fucoidan-P-selectin binding and selectively releases MA-5 within the high-ROS microenvironment via thioketal linker cleavage. This enhanced delivery potently restores mitochondrial membrane potential and ATP production, scavenges excess ROS, and inhibits endothelial apoptosis. Consequently, Fuc-TP@MA-5 significantly attenuates pulmonary edema, vascular hyperpermeability, and inflammatory cytokine storm in a murine model of LPS-induced ALI, outperforming free MA-5. Our work establishes a targeted mitochondrial functional improvement strategy, offering a promising and intelligent nanotherapeutic paradigm for treating ALI and other vascular inflammatory disorders. Download: Download high-res image (166KB) Download: Download full-size image