Mesenchymal Stromal Cell-Based Cell-Drug Conjugates for the Treatment of Acute Liver Failure.

Acute liver failure (ALF) is a life-threatening syndrome characterized by severe inflammatory injury and high mortality. Mesenchymal stromal cells (MSCs) hold therapeutic promise for ALF because of their immunomodulatory and tissue-repair capacities. However, in the ALF inflammatory microenvironment, characterized by abundant activated M1 macrophages and elevated pro-inflammatory cytokines, MSCs are susceptible to apoptosis, resulting in low survival and limited therapeutic efficacy. Here, we combined the anti-inflammatory small-molecule rosiglitazone with MSCs to construct a cell-drug conjugate (CDC) using MSCs as cellular carriers. Rosiglitazone was encapsulated within nanoparticles coated with neutrophil membranes and anchored onto the MSC surface. Sustained release of rosiglitazone from the MSC surface intrinsically enhanced MSC proliferation and paracrine activity through PI3K-Akt pathway activation and extrinsically modulated the inflammatory microenvironment by promoting macrophage polarization toward an anti-inflammatory phenotype. In a mouse model of ALF, rosiglitazone nanoparticle-modified MSCs exhibited enhanced accumulation and prolonged retention in the injured liver, more effectively inhibited hepatocyte apoptosis and promoted hepatocyte proliferation, thereby achieving superior therapeutic efficacy. Thus, our study provides a promising strategy for enhancing MSC-based therapy in ALF.