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

Abstract 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 (S ₁₀ L ₁₂ S ₁₀ ) and curved sheet‐forming GA‐(PSar) ₂₄ ‐ b ‐( l ‐Leu‐Aib) ₇ (S ₂₆ L ₁₄ ), which GA, PSar, Leu and Aib mean glycolic acid, polysarcosine, leucine and α‐aminoisobutyric acid. The PCV is successfully constructed from a mixture of S ₁₀ L ₁₂ S ₁₀ and S ₂₆ L ₁₄ in molar ratios of 2:1 and 1:1. In addition, curved S ₂₆ L ₁₄ membrane forms edges and corners, while planar S ₁₀ L ₁₂ S ₁₀ 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.