This study was conducted to investigate the protective effect of platelet-rich plasma-derived exosomes (PRP-Exos) in diabetic wound healing, as well as the involved molecular mechanism. Exosomes collected from PRP were extracted and identified, then the promoting effect on diabetic wound healing was tested in high glucose and lipopolysaccharide (HL)-induced RAW264.7 cells and excisional wound models constructed in streptozotocin-induced diabetic SD rats. PRP-Exos showed the best capacity for accelerating wound healing in the diabetic rat model. Cell proliferation of RAW264.7 cells was effectively facilitated after HL treatment, while PRP-Exos implemented could obviously eliminate the HL effect on RAW264.7 cells. The protein expression levels of PINK1, parkin, and LC3I/LC3II were both obviously diminished, and the expression of kininogen-1 (KNG1) was obviously increased in HL-induced RAW264.7 cells, while the opposite results were observed after PRP-Exos treatment. HL treatment could remarkably suppress the protein expression levels of p-PI3K/PI3K and p-AKT/AKT in RAW264.7 cells, while PRP-Exos administration could reverse this trend. Interestingly, KNG1 upregulation could effectively reverse the effect of PRP-Exos on the tumor necrosis factor-alpha and high mobility histone 1 levels, protein expression of p-PI3K/PI3K and p-AKT/AKT, and mitophagy-related markers in HL-induced RAW264.7 cells. In conclusion, PRP-Exos facilitated macrophage mitophagy in diabetic wound healing by targeting KNG1 via PI3K–AKT pathway.
BakadiaBM, Qaed AhmedAA, LamboniL, et al.Engineering homologous platelet-rich plasma, platelet-rich plasma-derived exosomes, and mesenchymal stem cell-derived exosomes-based dual-crosslinked hydrogels as bioactive diabetic wound dressings. Bioact Mater, 2023; 28:74–94; doi: 10.1016/j.bioactmat.2023.05.002
2.
CaiF, WangP, YuanM, et al.Hypoxic microenvironment promotes diabetic wound healing by polarizing macrophages to the M2 phenotype in vivo. J Mol Histol, 2024; 55(5):967–976; doi: 10.1007/s10735-024-10244-y
3.
CaoW, MengX, CaoF, et al.Exosomes derived from platelet-rich plasma promote diabetic wound healing via the JAK2/STAT3 pathway. iScience, 2023a;26(11):108236; doi: 10.1016/j.isci.2023.108236
4.
CaoY, XiongJ, GuanX, et al.Paeoniflorin suppresses kidney inflammation by regulating macrophage polarization via KLF4-mediated mitophagy. Phytomedicine, 2023b;116:154901; doi: 10.1016/j.phymed.2023.154901
5.
DaiZZ, XuJ, ZhangQ, et al.TREM1 interferes with macrophage mitophagy via the E2F1-mediated TOMM40 transcription axis in rheumatoid arthritis. Free Radic Biol Med, 2025; 228:267–280; doi: 10.1016/j.freeradbiomed.2025.01.013
6.
DalmedicoMM, do Rocio FedaltoA, MartinsWA, et al.Effectiveness of negative pressure wound therapy in treating diabetic foot ulcers: A systematic review and meta-analysis of randomized controlled trials. Wounds, 2024; 36(8):281–289; doi: 10.25270/wnds/23140
7.
DwivediJ, SachanP, WalP, et al.Current state and future perspective of diabetic wound healing treatment: Present evidence from clinical trials. Curr Diabetes Rev, 2024; 20(5):e280823220405; doi: 10.2174/1573399820666230828091708
8.
FanY, PionneauC, CocozzaF, et al.Differential proteomics argues against a general role for CD9, CD81 or CD63 in the sorting of proteins into extracellular vesicles. J Extracell Vesicles, 2023; 12(8):e12352; doi: 10.1002/jev2.12352
9.
FangCJ, RongXJ, JiangWW, et al.Geniposide promotes wound healing of skin ulcers in diabetic rats through PI3K/Akt pathway. Heliyon, 2023; 9(11):e21331; doi: 10.1016/j.heliyon.2023.e21331
10.
FangX, ShaoZ, DingH, et al.Urolithin A enhances diabetic wound healing: Insights from parkin-mediated mitophagy in endothelial progenitor cells. Int Immunopharmacol, 2025; 155:114572; doi: 10.1016/j.intimp.2025.114572
11.
FurnissSK, YaoR, GonzalezG. Automatic gene prioritization in support of the inflammatory contribution to Alzheimer’s disease. AMIA Jt Summits Transl Sci Proc, 2014; 2014:42–47.
12.
GomezPT, AndrewsKL, ArthursJR, et al.Platelet-rich plasma in the treatment of diabetic foot ulcers. Adv Skin Wound Care, 2024; 37(11&12):608–615; doi: 10.1097/asw.0000000000000229
13.
GuoSC, TaoSC, YinWJ, et al.Exosomes derived from platelet-rich plasma promote the re-epithelization of chronic cutaneous wounds via activation of YAP in a diabetic rat model. Theranostics, 2017; 7(1):81–96; doi: 10.7150/thno.16803
14.
GuptaAK, WangT, RapaportJA, et al.Therapeutic potential of extracellular vesicles (exosomes) derived from platelet-rich plasma: A literature review. J Cosmet Dermatol, 2025; 24(2):e16709; doi: 10.1111/jocd.16709
15.
HeL, ZhaoN, ChenX, et al.Platelet-rich plasma-derived exosomes accelerate the healing of diabetic foot ulcers by promoting macrophage polarization toward the M2 phenotype. Clin Exp Med, 2025; 25(1):163; doi: 10.1007/s10238-025-01651-w
16.
HuQ, WangQ, HanC, et al.Sufentanil attenuates inflammation and oxidative stress in sepsis-induced acute lung injury by downregulating KNG1 expression. Mol Med Rep, 2020; 22(5):4298–4306; doi: 10.3892/mmr.2020.11526
17.
HuS, ShenF, JiaN, et al.Novel monomers recipe derived from Shengji-Huayu formula targeting PI3K/Akt signaling pathway for diabetic wound healing based on accurate network pharmacology. J Ethnopharmacol, 2025; 344:119509; doi: 10.1016/j.jep.2025.119509
18.
HuangJ, ChenX, LvY. HMGB1 mediated inflammation and autophagy contribute to endometriosis. Front Endocrinol (Lausanne), 2021; 12:616696; doi: 10.3389/fendo.2021.616696
19.
JinW, ChenX, KongL, et al.Gene therapy targeting inflammatory pericytes corrects angiopathy during diabetic wound healing. Front Immunol, 2022; 13:960925; doi: 10.3389/fimmu.2022.960925
20.
KöhlerJ, MaletzkiC, KoczanD, et al.Kininogen supports inflammation and bacterial spreading during Streptococcus pyogenes sepsis. EBioMedicine, 2020; 58:102908; doi: 10.1016/j.ebiom.2020.102908
21.
KunL, YunpengD, ShuyuanF. Mechanism of DT-13 regulating macrophages in diabetic wound healing. Cell Signal, 2024; 124:111446; doi: 10.1016/j.cellsig.2024.111446
22.
LvD, CaoX, ZhongL, et al.Targeting phenylpyruvate restrains excessive NLRP3 inflammasome activation and pathological inflammation in diabetic wound healing. Cell Rep Med, 2023; 4(8):101129; doi: 10.1016/j.xcrm.2023.101129
23.
MłynarskaE, CzarnikW, DzieżaN, et al.Type 2 diabetes mellitus: New pathogenetic mechanisms, treatment and the most important complications. Int J Mol Sci, 2025; 26(3):1094; doi: 10.3390/ijms26031094
24.
NieX, LiuY, YuanT, et al.Platelet-rich plasma-derived exosomes promote blood-spinal cord barrier repair and attenuate neuroinflammation after spinal cord injury. J Nanobiotechnology, 2024; 22(1):456; doi: 10.1186/s12951-024-02737-5
25.
OputaRN, OputaPU. Chronic complications of diabetes mellitus. West Afr J Med, 2024; 41(8):904–908.
26.
QiW, JinL, HuangS, et al.Modulating synovial macrophage pyroptosis and mitophagy interactions to mitigate osteoarthritis progression using functionalized nanoparticles. Acta Biomater, 2024; 181:425–439; doi: 10.1016/j.actbio.2024.05.014
27.
ShiH, ZhangZ, YuanX, et al.PROS1 is a crucial gene in the macrophage efferocytosis of diabetic foot ulcers: A concerted analytical approach through the prisms of computer analysis. Aging (Albany NY), 2024; 16(8):6883–6897; doi: 10.18632/aging.205732
28.
ShiK, ChenX, XieB, et al.Celastrol alleviates chronic obstructive pulmonary disease by inhibiting cellular inflammation induced by cigarette smoke via the Ednrb/Kng1 signaling pathway. Front Pharmacol, 2018; 9:1276; doi: 10.3389/fphar.2018.01276
29.
ShuQH, ZuoRT, ChuM, et al.Fiber-reinforced gelatin/β-cyclodextrin hydrogels loaded with platelet-rich plasma-derived exosomes for diabetic wound healing. Biomater Adv, 2023; 154:213640; doi: 10.1016/j.bioadv.2023.213640
30.
SinghA, ShadangiS, GuptaPK, et al.Type 2 diabetes mellitus: A comprehensive review of pathophysiology, comorbidities, and emerging therapies. Compr Physiol, 2025; 15(1):e70003; doi: 10.1002/cph4.70003
31.
WangJ, WuH, PengY, et al.Hypoxia adipose stem cell-derived exosomes promote high-quality healing of diabetic wound involves activation of PI3K/Akt pathways. J Nanobiotechnology, 2021; 19(1):202; doi: 10.1186/s12951-021-00942-0
32.
WangS, WuJ, RenK, et al.Platelet-rich plasma-derived exosome-encapsulated hydrogels accelerate diabetic wound healing by inhibiting fibroblast ferroptosis. ACS Appl Mater Interfaces, 2025; 17(19):27923–27936; doi: 10.1021/acsami.5c02705
33.
WidigdoDAM, SofroZM, PangastutiHS, et al.The efficacy of negative pressure wound therapy (NPWT) on healing of diabetic foot ulcers: A literature review. Curr Diabetes Rev, 2024; 20(8):1–11; doi: 10.2174/0115733998229877230926073555
YangC, HanJ, LiuH, et al.Storage of plasma-derived exosomes: Evaluation of anticoagulant use and preserving temperatures. Platelets, 2024; 35(1):2337255; doi: 10.1080/09537104.2024.2337255
36.
YeZ, YuanY, KuangG, et al.Platelet-rich plasma and corticosteroid injection for tendinopathy: A systematic review and meta-analysis. BMC Musculoskelet Disord, 2025; 26(1):339; doi: 10.1186/s12891-025-08566-3
37.
ZhangC, XiangJ, WangG, et al.Salvianolic acid B improves diabetic skin wound repair through Pink1/Parkin-mediated mitophagy. Arch Physiol Biochem, 2025; 131(1):40–51; doi: 10.1080/13813455.2024.2387693
38.
ZhangQ, ZhuW, ZouZ, et al.A preliminary study in immune response of BALB/c and C57BL/6 mice with a locally allergic rhinitis model. Am J Rhinol Allergy, 2023; 37(4):410–418; doi: 10.1177/19458924231157619
39.
ZhangY, LiW, ZhouY. Identification of hub genes in diabetic kidney disease via multiple-microarray analysis. Ann Transl Med, 2020; 8(16):997; doi: 10.21037/atm-20-5171
40.
ZhongH, WangF, TangC, et al.Combination of structural analysis and proteomics strategy revealed the mechanism of ultrasound-assisted cold plasma regulating shrimp allergy. J Agric Food Chem, 2024:22893–22907; doi: 10.1021/acs.jafc.4c06388
41.
ZhouX, GuoY, YangK, et al.The signaling pathways of traditional Chinese medicine in promoting diabetic wound healing. J Ethnopharmacol, 2022; 282:114662; doi: 10.1016/j.jep.2021.114662
42.
ZhouX, GuoYL, XuC, et al.Macrophages: Key players in diabetic wound healing. World J Diabetes, 2024; 15(11):2177–2181; doi: 10.4239/wjd.v15.i11.2177
43.
ZhuH, JianZ, ZhongY, et al.Janus kinase inhibition ameliorates ischemic stroke injury and neuroinflammation through reducing NLRP3 inflammasome activation via JAK2/STAT3 pathway inhibition. Front Immunol, 2021; 12:714943; doi: 10.3389/fimmu.2021.714943
