Nanofibril-Structured Granular Hydrogels Harness Stem Cell Retention and Immunoregulation in Diabetic Microenvironment

Granular hydrogel matrices have shown significant advantages in mesenchymal stem cell (MSC) delivery and tissue ingrowth due to their minimally invasive injection capabilities and porous structures. However, creating granular hydrogels that simultaneously mimic the nanofilamentous architecture of the natural extracellular matrix (ECM) and enhance stem cell retention and in vivo immunoregulation in a diabetic microenvironment remains challenging. In this study, we present a nanoengineered supramolecular granular hydrogel with a nanofibrillar structure designed to improve stem cell retention and regulate immune responses under diabetic conditions. The granular hydrogel matrix is assembled based on multiple hydrogen bonding and hydrophobic interactions, exhibiting a range of tunable features, including shear-thinning, injectability, self-healing, and 3D printability. Furthermore, enriched with manganese dioxide (MnO₂)-amyloid fibril (AF) nanohybrids, the granular hydrogel supports MSC adhesion and stemness maintenance and can modulate the reactive oxygen species microenvironment by converting H₂O₂ into oxygen, thereby promoting cell viability and osteogenic differentiation of MSCs with the sustained release of Mn²⁺. In a two-week diabetic rat model study, the granular hydrogel demonstrates enhanced in vivo cell retention and anti-inflammatory immunomodulation properties, underscoring its potential as a promising matrix for stem cell therapy and immune regulation in diabetic conditions.