Carbon Nanotubes Promote the Development of Intestinal Organoids through Regulating Extracellular Matrix Viscoelasticity and Intracellular Energy Metabolism.

The biological effect of engineered carbon nanotubes (CNTs) as beneficial biomaterials on the intestine, especially on its development, remains unclear. Here, we investigated the profitable effect of CNTs with a different graphene layer and surface modification on the 3D model of intestinal organoids and demonstrated that CNTs (50 μg/mL) promoted the development of intestinal organoids over time (0-5 days). The mechanisms involve the modulation of extracellular matrix (ECM) viscoelasticity and intracellular energy metabolism. In particular, CNTs reduced the hardness of the extracellular matrix through decreasing the elasticity and increasing the viscosity as a result of elevated metalloproteinase and binding to a protein scaffold, which activated the mechanical membrane sensors of cells, Piezo, and downstream P-p38-yes-associated protein (YAP) pathway. Moreover, CNTs altered the metabolic profile of intestinal organoids and induced increased mitochondria activity, respiration, and nutrient absorption. These mechanisms cooperated with each other to promote the proliferation and differentiation of intestinal organoids. In addition, the promoted effect of CNTs is highly dependent on the number of graphene layers, manifested as multiwalled CNTs > single-walled CNTs. Our findings highlight the CNT-intestine interaction and imply the potential of CNTs as biomaterials for intestine-associated tissue engineering.