Shear-responsive peptide/siRNA complexes as lung-targeting gene vectors

All de novo designed cationic peptides can form complexes with siRNA and effectively accumulate in lung. However, only the peptide/siRNA complexes that exhibit weak interaction with serum components and can be broken down at shear rate above certain value avoid the inflammation and death caused by pulmonary embolism. Particles administrated intravenously will pass through the pulmonary capillary network before being distributed to the body. Therefore, fabrication of vectors sensitive to blood shear and active with blood components should be a practical approach to develop lung-targeting gene carriers self-regulated by circulatory system. In this work, we designed a series of cationic peptides with the same charge density but varying hydrophobicity and capacity to form hydrogen bonds, and investigated their ability to form complexes with siRNA, the behaviours of peptide/siRNA complexes in the presence of serum under shear, and the lung-targeting efficacy of the complexes regulated by blood. The hydrophobic interaction controls the complexation between peptide and siRNA, while the hydrogen bonds are responsible for the binding of peptides to the serum components in blood. In vivo tests show that all the peptide/siRNA complexes can accumulate in lung. However, only the complexes that exhibit weak interaction with serum components and can be broken down by shear avoid the inflammation and death caused by pulmonary embolism. Moreover, the peptide with strong hydrophobicity can retain siRNA in lung without early release of the cargo. Our study provides a step toward the development of adaptive gene carriers under the regulation of circulatory system.