Single-cell encapsulation of mesenchymal stromal cells <i>via</i> ECM-mimetic supramolecular hydrogels enhances therapeutic efficacy

Mesenchymal stromal cells (MSCs) hold great promise for tissue regeneration due to their potent paracrine effects. However, the absence of extracellular matrix (ECM) support following transplantation significantly compromises their survival and therapeutic efficacy. To address this, we developed a single-cell encapsulation strategy using an ECM-mimetic supramolecular hydrogel system based on host-guest chemistry. In this approach, cholesterol-polyethylene glycol-adamantane is inserted into the MSC membrane <i>via</i> hydrophobic interactions, enabling the subsequent formation of a uniform hydrogel coating through specific recognition between cyclodextrin- and adamantane-modified hyaluronic acids. This facile and biocompatible strategy achieves high encapsulation efficiency without the need for complex equipment, while preserving cell viability and function. Encapsulated MSCs exhibited enhanced resistance to pathological stress, improved survival, and superior therapeutic efficacy in a rat model of myocardial infarction. These findings highlight the potential of supramolecular single-cell encapsulation to augment MSC-based therapies for tissue repair and regenerative medicine.