Thiolated Nanovesicles Integrating Mucolytics for Efficient Lung Mucus Penetration and Acute Lung Injury Therapy

Mucolytics provide an effective therapeutic strategy for promoting drug penetration into mucus layers in treating acute lung injury (ALI). However, for an ideal therapeutic system, how to further achieve targeted delivery in a mucolytics therapeutic system remains a challenge. Herein, we utilized indocyanine green (ICG) and two cationic pillar arenes (CWP[5] and CWP[6]) to synthesize two types of pH-responsive nanovesicles through host–guest reactions (ICG-CWP[5] and ICG-CWP[6]). And then we connected them with copolymers (Man@Cys) to obtain thiolated nanovesicles (ICG-CWP[5]/[6]MC), which endowed nanovesicles with targeting capability. In vitro and in vivo, ICG-CWP[5]MC and ICG-CWP[6]MC not only demonstrated mucus penetration but also demonstrated targeted delivery of CCR2-siRNA into lung mononuclear macrophages through cell imaging and near-infrared (NIR) imaging. Notably, among those, ICG-CWP[5]MC showed superior delivery efficiency due to smaller size. Then, the therapeutic system with local administration effectively inhibited the inflammatory response of macrophages, with the CCR2-siRNA specifically silencing the chemokine receptor. And it exhibited higher efficiency in treatment of ALI by inhibiting the pulmonary inflammatory injury. Overall, the thiolated nanovesicles provide new drug delivery to the lungs for improving the treatment effect of pneumonia.