Supramolecular Chiral Nanofibers Activated Pro‐Survival Autophagy: An Extracellular Strategy for Hypoxic Cell Protection

Abstract Hypoxic injury poses a severe threat to cell survival. Activation of pro‐survival autophagy via autophagy‐inducing nanomaterials (AINMs) has emerged as one of the most promising therapeutic strategies. However, internalized AINMs easily bind with intracellular lysosomes, resulting in disruptive effects on autophagic flux and limited pro‐survival effects. Herein, inspired by the naturally existing chiral structures in actin membrane protein, two nanofibers based on achiral pyridine‐substituted coumarin derivatives (PyC) with only difference in supramolecular chirality are constructed by the method of chirality memory to activate autophagy extracellularly. The high degree of conformational chirality matching between right‐handed PyC‐r nanofibers and actin ensures an enhanced stereoselective interaction between the pyridine groups on PyC and the hydroxyl groups on serine‐rich Girdin protein (an actin‐binding protein involved in cell survival). This stereoselective interaction can activate the autophagy‐related Akt/mTOR pathway via mechanical signal transmission and phosphorylation of Akt, which avoids the disruption of autophagic flux and significantly mitigates cellular hypoxic injury. In a rat myocardial ischemia model, scar formation and functional deterioration are particularly alleviated by injection of PyC‐r nanofibers into murine infarcted myocardium. The findings pioneeringly establish a direct link between chiral biomedical materials and cellular autophagy, offering novel insights for cellular hypoxic protection.