Abstract

Diabetes impairs wound healing due to hyperglycemia-induced vascular dysfunction. This condition triggers mitochondrial impairment, leading to ferroptosis in endothelial cells. While mesenchymal stromal cells (MSCs) can promote tissue repair through intercellular mitochondrial transfer, strategies to enhance their mitochondrial-donating capacity under hyperglycemic conditions remain underdeveloped. Mesenchymal condensation endows MSCs with enhanced regenerative potential and greater mitochondrial functionality. Microcarrier-based three-dimensional (3D) dynamic culture systems mimicking this process offer a promising strategy. However, effectively shielding donor MSCs from hyperglycemia-induced oxidative stress remains a key challenge in microcarrier design. Here, we engineered a glucose-responsive antioxidant biomaterial-based 3D dynamic culture system using chitosan-formylphenylboronic acid (CS-FPBA) microcarriers combined with stem cells from human exfoliated deciduous teeth (SHED) to generate native-like SHED (N-SHED). This system provides a protective niche for transplanted SHED through glucose-triggered antioxidant microcarrier degradation while simultaneously enhancing mitochondrial function and intercellular transfer. Consequently, N-SHED attenuated endothelial ferroptosis, promoted angiogenesis, and accelerated diabetic wound healing in vivo. This study presents a native-like cell culture platform that amplifies the therapeutic efficacy of MSCs by enhancing their mitochondrial-donating capacity. With strong translational potential, this strategy not only advances MSCs-based therapy for diabetic wounds but also offers a novel framework for mitochondrial-targeted regenerative medicine.