Work

Polysaccharide-engineered mitochondria reprogram macrophages to resolve diabetic wound inflammation and promote repair

Year: 2026

Type: article

Abstract: Chronic diabetic wounds are characterized by persistent inflammation, defective resolution and impaired tissue regeneration, in which macrophage dysfunction and mitochondrial damage play central roles. Here, we developed a macrophage-targeted engineered mitochondrial transplantation system by coating adipose-derived stem cell (ADSC) mitochondria with triphenylphosphonium-modified konjac glucomannan (Mito-TPP-KGM). This design preserves mitochondrial membrane potential and ATP production while reducing ROS generation, and provides a mannose-rich corona for lectin receptor-related uptake. In RAW264.7 macrophages exposed to high glucose plus H 2 O 2 or LPS, Mito-TPP-KGM is efficiently internalized, restores mitochondrial homeostasis, rebalances glycolysis and oxidative phosphorylation, and shifts inflammatory profiles toward a less inflammatory and more reparative phenotype. Engineered mitochondria also restore efferocytosis of apoptotic neutrophil-like cells and enhance the pro-angiogenic capacity of macrophage-conditioned media, thereby improving endothelial tube formation, migration and proliferation. Blocking experiments with mannan and anti-CD206/anti-DC-SIGN antibodies, together with species-specific mtDNA quantification, indicate that mannose-type lectin receptors contribute to the uptake and immunomodulatory effects of Mito-TPP-KGM. In a db/db mouse full-thickness wound model, local delivery of Mito-TPP-KGM promotes wound repair, improves histological healing, reduces oxidative damage, enhances angiogenesis, and modulates wound macrophage phenotype, leading to accelerated wound closure; these therapeutic benefits are partially attenuated by local CD206 blockade. Collectively, these findings demonstrate that polysaccharide-engineered mitochondria can reprogram diabetic wound macrophages via targeted mitochondrial transplantation, offering a promising immunometabolic strategy for chronic wound therapy. • Engineered Mito-TPP-KGM preserves mitochondrial bioenergetics and promotes macrophage uptake via lectin receptors. • Mito-TPP-KGM restores macrophage mitochondrial membrane potential, lowers ROS, and rebalances metabolism. • Mito-TPP-KGM enhances macrophage efferocytosis and pro-angiogenic paracrine signaling to improve endothelial repair. • In db/db mice, Mito-TPP-KGM shows macrophage-biased wound uptake, reduces oxidative damage, and accelerates wound healing.

Source: Bioactive Materials

DOI: 10.1016/j.bioactmat.2026.04.009