Engineered mesenchymal stromal cells with bispecific polyvalent peptides suppress excessive neutrophil infiltration and boost therapy.

Abstract

Excessive neutrophil infiltration can exacerbate inflammation and tissue damage, contributing to conditions like autoimmune disorders and liver diseases. Mesenchymal stromal cells (MSCs) share homing mechanisms with neutrophils, showing promise for treating such diseases. However, ex vivo expanded MSCs often suffer from reduced homing efficiency due to the loss of essential ligands. Here, we engineer MSCs with P-selectin and E-selectin targeting peptides, assembling them into bispecific polyvalent structures using DNA self-assembly technology. This modification allows engineered MSCs to compete with chemotactic neutrophils for selectin binding sites on endothelial cells. In a mouse model of acute liver failure, engineered MSCs effectively home to the damaged liver and substantially inhibit excessive neutrophil infiltration. The combination of inhibiting neutrophil infiltration and the MSCs' inherent therapeutic properties lead to superior therapeutic outcomes. Single-cell RNA sequencing reveals that engineered MSCs elevate the levels of Marco_macrophage, which have neutrophil-inhibitory effects. Our study offers a perspective for advancing MSC-based therapies in tissue repair.