Shear Stress-Responsive Peptide Cubic Vesicles Assembled from Membranes with Different Curvatures

Stenotic blood vessels differ from normal blood vessels in that the blood flow shear stress is increased to a higher order of magnitude. Therefore, drug delivery systems (DDSs) capable of responding to changes in the shear stress are highly desirable. To prepare sheer stress-responsive carriers, a peptide cubic vesicle (PCV) is prepared by combining two types of sheet-forming amphiphilic polypeptides: planar sheet-forming GA-(PSar)₁₀-b-(l-Leu-Aib)₆-b-(PSar)₁₀-GA (S₁₀L₁₂S₁₀) and curved sheet-forming GA-(PSar)₂₄-b-(l-Leu-Aib)₇ (S₂₆L₁₄), which GA, PSar, Leu and Aib mean glycolic acid, polysarcosine, leucine and α-aminoisobutyric acid. The PCV is successfully constructed from a mixture of S₁₀L₁₂S₁₀ and S₂₆L₁₄ in molar ratios of 2:1 and 1:1. In addition, curved S₂₆L₁₄ membrane forms edges and corners, while planar S₁₀L₁₂S₁₀ membrane forms the faces of the PCV. Notably, the PCV deforms under pathological shear stress conditions (10 Pa) but retains its original structure under the normal physiological shearing force of 1 Pa. Moreover, the PCV releases 84% of its encapsulated cargo in response to simulated pathological flow. Targeting the changing biophysical environment for drug development has the potential to shift the paradigm for treating vascular occlusion-inducing diseases from biochemical to mechanical stimulation, thereby lowering the required dose and side effects of drugs while maximizing their therapeutic efficacy.