Dendrimer-Mediated Intracellular Delivery of Fibronectin Guides Macrophage Polarization to Alleviate Acute Lung Injury

Fibronectin (FN) is an essential glycoprotein in the extracellular matrix with favorable biological functions for potential applications in various biomedical fields including wound healing, regenerative medicine, tissue engineering, as well as diagnosis and treatment of cancer and inflammatory diseases. Herein, we aim to explore the influence of intracellular FN delivery on macrophage functions and its possible therapeutic applications. We prepared phenylboronic acid (PBA)-functionalized generation 5 (G5) poly(amidoamine) dendrimers (G5.NH2-PBA) as a nanocarrier to load FN, and reveal that the obtained dendrimers enable efficient intracellular delivery of FN at an optimized dendrimer-toFN weight ratio of 8, which guides macrophages toward antiinflammatory M2 phenotype polarization. Studies on action mechanisms show that the dendrimer-mediated FN intracellular delivery acts strongly on suppressing the nuclear factor -KB pathway, leading to reduced pro-inflammatory cytokine secretion and enhanced reactive oxygen species depletion in lipopolysaccharide (LPS)-activated macrophages. Further investigation in vivo using an LPSinduced mouse model of acute lung injury (ALI) shows that the dendrimer-mediated FN delivery can effectively alleviate the ALI symptoms through alleviation of lung inflammation and oxidation stress. Our work suggests a general approach to using dendrimers for mediating intracellular delivery of FN, thereby offering many opportunities to explore the biological functions of FN for different therapeutic applications toward inflammation-associated diseases.