PMID- 34942563 OWN - NLM STAT- MEDLINE DCOM- 20220314 LR - 20231206 IS - 1878-5905 (Electronic) IS - 0142-9612 (Linking) VI - 280 DP - 2022 Jan TI - Bioinspired design of mannose-decorated globular lysine dendrimers promotes diabetic wound healing by orchestrating appropriate macrophage polarization. PG - 121323 LID - S0142-9612(21)00679-7 [pii] LID - 10.1016/j.biomaterials.2021.121323 [doi] AB - A large number of cytokines or growth factors have been used in the treatment of inflammation. However, they are highly dependent on an optimal delivery system with sufficient loading efficiency and protection of growth factors from proteolytic degradation. To develop the immunotherapy capacity of peptide dendrimers themselves, inspired by the structure and immunoregulatory functions of mannose-capped lipoarabinomannan (ManLAM), we thus propose a hypothesis that mannose-decorated globular lysine dendrimers (MGLDs) with precise molecular design can elicit anti-inflammatory activity through targeting and reprogramming macrophages to M2 phenotype. To achieve this, a series of mannose-decorated globular lysine dendrimers (MGLDs) was developed. Size-controlled MGLDs obtained were spherical with positive surface charges. The mean size ranged from 50-200 nm in varying generations and modification degrees. The initial screening study revealed that MGLDs have superior biocompatibility. When cocultured with MGLDs, mouse bone marrow-derived macrophages (BMDMs) acquired an anti-inflammatory M2 phenotype characterized by significant mannose receptor (MR) clustering on the cell surface and the elongated shape, an increased production of transforming growth factor (TGF)-beta1, interleukin (IL)-4 and IL-10, a downregulated secretory of IL-1beta, IL-6, and tumor necrosis factor (TNF)-alpha, and increased ability to induce fibroblast proliferation. Then in vivo studies further demonstrated that topical administration of optimized MGLDs accelerates wound repair of full-thickness cutaneous defects in type 2 diabetic mice via M2 macrophage polarization. Mechanistically, MGLDs treatment showed an enhanced closure rate, collagen deposition, and angiogenesis, along with mitigated inflammation modulated by a suppressed secretory of pro-inflammation cytokines, and increased production of TGF-beta1. These findings provide the first evidence that the bioinspired design of MGLDs can direct M2 macrophage polarization, which may be beneficial in the therapy of injuries and inflammation. CI - Copyright (c) 2021 Elsevier Ltd. All rights reserved. FAU - Jiang, Yuhang AU - Jiang Y AD - Research Institute for Biomaterials, Tech Institute for Advanced Materials, College of Materials Science and Engineering, NJTech-BARTY Joint Research Center for Innovative Medical Technology, Suqian Advanced Materials Industry Technology Innovation Center, Jiangsu Collaborative Innovation Center for Advanced Inorganic Function Composites, Nanjing Tech University, Nanjing, 211816, PR China. FAU - Zhao, Wentao AU - Zhao W AD - Research Institute for Biomaterials, Tech Institute for Advanced Materials, College of Materials Science and Engineering, NJTech-BARTY Joint Research Center for Innovative Medical Technology, Suqian Advanced Materials Industry Technology Innovation Center, Jiangsu Collaborative Innovation Center for Advanced Inorganic Function Composites, Nanjing Tech University, Nanjing, 211816, PR China. FAU - Xu, Shuangshuang AU - Xu S AD - Research Institute for Biomaterials, Tech Institute for Advanced Materials, College of Materials Science and Engineering, NJTech-BARTY Joint Research Center for Innovative Medical Technology, Suqian Advanced Materials Industry Technology Innovation Center, Jiangsu Collaborative Innovation Center for Advanced Inorganic Function Composites, Nanjing Tech University, Nanjing, 211816, PR China. FAU - Wei, Jingjing AU - Wei J AD - Research Institute for Biomaterials, Tech Institute for Advanced Materials, College of Materials Science and Engineering, NJTech-BARTY Joint Research Center for Innovative Medical Technology, Suqian Advanced Materials Industry Technology Innovation Center, Jiangsu Collaborative Innovation Center for Advanced Inorganic Function Composites, Nanjing Tech University, Nanjing, 211816, PR China. FAU - Lopez Lasaosa, Fernando AU - Lopez Lasaosa F AD - Research Institute for Biomaterials, Tech Institute for Advanced Materials, College of Materials Science and Engineering, NJTech-BARTY Joint Research Center for Innovative Medical Technology, Suqian Advanced Materials Industry Technology Innovation Center, Jiangsu Collaborative Innovation Center for Advanced Inorganic Function Composites, Nanjing Tech University, Nanjing, 211816, PR China; Department of Animal Pathology, Veterinary Faculty, University of Zaragoza, Zaragoza, 50013, Spain. FAU - He, Yiyan AU - He Y AD - Research Institute for Biomaterials, Tech Institute for Advanced Materials, College of Materials Science and Engineering, NJTech-BARTY Joint Research Center for Innovative Medical Technology, Suqian Advanced Materials Industry Technology Innovation Center, Jiangsu Collaborative Innovation Center for Advanced Inorganic Function Composites, Nanjing Tech University, Nanjing, 211816, PR China. Electronic address: yiyanhe@njtech.edu.cn. FAU - Mao, Hongli AU - Mao H AD - Research Institute for Biomaterials, Tech Institute for Advanced Materials, College of Materials Science and Engineering, NJTech-BARTY Joint Research Center for Innovative Medical Technology, Suqian Advanced Materials Industry Technology Innovation Center, Jiangsu Collaborative Innovation Center for Advanced Inorganic Function Composites, Nanjing Tech University, Nanjing, 211816, PR China. FAU - Bolea Bailo, Rosa Maria AU - Bolea Bailo RM AD - Department of Animal Pathology, Veterinary Faculty, University of Zaragoza, Zaragoza, 50013, Spain. FAU - Kong, Deling AU - Kong D AD - Key Laboratory of Bioactive Materials for the Ministry of Education, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300071, PR China. FAU - Gu, Zhongwei AU - Gu Z AD - Research Institute for Biomaterials, Tech Institute for Advanced Materials, College of Materials Science and Engineering, NJTech-BARTY Joint Research Center for Innovative Medical Technology, Suqian Advanced Materials Industry Technology Innovation Center, Jiangsu Collaborative Innovation Center for Advanced Inorganic Function Composites, Nanjing Tech University, Nanjing, 211816, PR China; Huaxi MR Research Center (HMRRC), Department of Radiology, Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, 610041, PR China. Electronic address: zwgu@scu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20211215 PL - Netherlands TA - Biomaterials JT - Biomaterials JID - 8100316 RN - 0 (Dendrimers) RN - K3Z4F929H6 (Lysine) RN - PHA4727WTP (Mannose) SB - IM MH - Animals MH - *Dendrimers/metabolism MH - *Diabetes Mellitus, Experimental/pathology MH - Lysine MH - Macrophages/metabolism MH - Mannose/metabolism MH - Mice MH - Wound Healing OTO - NOTNLM OT - Bioinspired design OT - Diabetic wound healing OT - M2 macrophage polarization OT - Peptide dendrimers EDAT- 2021/12/24 06:00 MHDA- 2022/03/15 06:00 CRDT- 2021/12/23 20:27 PHST- 2021/07/25 00:00 [received] PHST- 2021/11/15 00:00 [revised] PHST- 2021/12/13 00:00 [accepted] PHST- 2021/12/24 06:00 [pubmed] PHST- 2022/03/15 06:00 [medline] PHST- 2021/12/23 20:27 [entrez] AID - S0142-9612(21)00679-7 [pii] AID - 10.1016/j.biomaterials.2021.121323 [doi] PST - ppublish SO - Biomaterials. 2022 Jan;280:121323. doi: 10.1016/j.biomaterials.2021.121323. Epub 2021 Dec 15.