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Publications

Journal Article Epublish

PubMed: 42011203 DOI: 10.1016/j.bioactmat.2026.04.009

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

Bioact Mater 63:484-505

Authors: Chenyan Yu, Qian Feng, Yuheng Liao, Meijun Tan, Yanzhi Zhao, Lang Chen, Wenqian Zhang, Chuanlu Lin, Ruiyin Zeng, Fawwaz Al-Smadi, Haochen Wang, Longyu Du, Xin Zhang, Ying Hu, Guodong Liu, Zhiyong Hou, Hang Xue, Guohui Liu

Affiliations

  • Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, China.
  • Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, China.
  • Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  • Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  • Department of Orthopedics, Key Laboratory of Structural Malformations in Children of Zhejiang Province, Key Laboratory of Orthopedics of Zhejiang Province, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.
  • Department of Orthopedics, Chongqing Hospital, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Chongqing, 400000, China.
  • Research group of Intelligent NanoEngineering, Department of Chemistry and Biochemistry, Mendel University in Brno, ZemÄ›dÄ›lská 1, 61300, Brno, Czech Republic.
  • Department of Wound Care Support, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China.
  • Department of Orthopaedic Surgery, Hebei Medical University Third Hospital, Shijiazhuang, Hebei, 050051, China. Engineering Research Center of Orthopedic Minimally Invasive Intelligent Equipment, China Ministry of Education, China. Key Laboratory of Biomechanics of Hebei Province, Shijiazhuang, Hebei, China. NHC Key Laboratory of Intelligent Orthopaedic Equipment, Shijiazhuang, Hebei, China. Key Laboratory of Precise Assessment, Diagnosis, and Treament of Soft Tissue Injury of Hebei Province, China.

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 2O 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.

MeSH

Cells, Mannose, Microscopy, Electron, Scanning Transmission, Polysaccharides, Macrophages, Phenotype, Mitochondria, Mannans, Therapeutics, Transplantation, Lectins