Polyphenol-Engineered Bimetal Oxides Promote Stem Cell Differentiation via Immune Microenvironment Reprogramming.

Abstract

Reprogramming the immune microenvironment is intricately associated with the regulation of stem cell behavior and tissue regeneration. However, precise control remains difficult due to complex immune-matrix interactions and limited multifunctional platforms. Herein, we report a polyphenol-engineered bimetallic oxide nanoplatform (MnCo₃O_<i>x</i>-TA) that enables coordinated immune modulation to direct stem cell differentiation. Mn doping and TA functionalization endow MnCo₃O_<i>x</i>-TA with an enhanced capacity to efficiently scavenge reactive oxygen and nitrogen species (ROS/RNS), thereby restoring the osteogenic potential of bone marrow mesenchymal stem cells (BMSCs) under inflammatory stress. It also reduces oxidative damage in inflamed tissues and shifts macrophages from pro-inflammatory (M1) to pro-regenerative (M2) phenotypes, reprogramming the immune microenvironment. Coculture experiments confirm that this immunoregulatory effect boosts osteogenic gene expression and differentiation. These results demonstrate that MnCo₃O_<i>x</i>-TA is a multifunctional antioxidant nanoplatform combining ROS/RNS scavenging with immune remodeling, offering a promising approach for immune-guided stem cell differentiation and tissue regeneration.