Chitosan thermosensitive hydrogel-based sustained-release system of Netrin-1 overexpressing macrophage exosomes: synergistic enhancement of angiogenesis and nerve regeneration
Source abstract
Abstract
Abstract Peripheral nerve injury (PNI) affects over 20 million individuals globally each year, with incomplete nerve regeneration presenting a significant socioeconomic burden, particularly in diabetic patients. M2 macrophages play a crucial role in nerve regeneration by promoting tissue remodeling and repair. However, the post-injury microenvironment impedes the stabilization of the M2 phenotype, limiting their therapeutic potential. In vitro experiments demonstrate that macrophages modified with Netrin-1 can be polarized toward the M2 phenotype. Exosomes secreted by these Netrin-1-modified macrophages (N-Exos) significantly enhance endothelial cell proliferation, migration, tube formation, and survival under hyperglycemic conditions. The underlying mechanism is likely mediated by the activation of the PI3K/AKT/mTOR pathway through Unc5b. To further enhance the therapeutic effects of N-Exos, we incorporated these exosomes into a berberine-modified chitosan-based hydrogel (NE@CSB), thereby developing an innovative synergistic therapeutic approach. The NE@CSB hydrogel demonstrates favorable injectability, thermoresponsive sol-gel transition, strong tissue adhesion, and sustained release of exosomes. In the sciatic nerve injury model of diabetic mice, blood flow perfusion and histological analysis of injured nerves demonstrated that NE@CSB hydrogel could effectively enhanced angiogenesis and sciatic nerve regeneration. Overall, NE@CSB presents a promising and safe therapeutic strategy for the clinical treatment of diabetic PNI.
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Research context
OpenAlex topics: Nerve injury and regeneration · Neurogenesis and neuroplasticity mechanisms · Axon Guidance and Neuronal Signaling
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
References (48)
Show source-provided references
1. Lopes, B. et al. Peripheral nerve injury treatments AND advances: one health perspective. Int. J. Mol. Sci. 23, 918 (2022).10.3390/ijms23020918 ↗
2. Namini, M. S. et al. Cell-free therapy based on extracellular vesicles: a promising therapeutic strategy for peripheral nerve injury. Stem Cell Res. Ther. 14, 254 (2023).10.1186/s13287-023-03467-5 ↗
3. Yu, T. et al. Exosomes as a promising therapeutic strategy for peripheral nerve injury. Curr. Neuropharmacol. 19, 2141–2151 (2021).10.2174/1570159X19666210203161559 ↗
4. Fan, B. et al. Mesenchymal stromal cell-derived exosomes ameliorate peripheral neuropathy in a mouse model of diabetes. Diabetologia 63, 431–443 (2019).10.1007/s00125-019-05043-0 ↗
5. Wang, G. et al. Blood vessel remodeling in late stage of vascular network reconstruction is essential for peripheral nerve regeneration. Bioeng. Transl. Med. 7, e10361 (2022).10.1002/btm2.10361 ↗
6. Huang, J. et al. Endothelial cell-derived exosomes boost and maintain repair-related phenotypes of Schwann cells via miR199-5p to promote nerve regeneration. J. Nanobiotechnology 21, 10 (2023).10.1186/s12951-023-01767-9 ↗
7. Zhu, D. et al. Macrophage M2 polarization induced by exosomes from adipose-derived stem cells contributes to the exosomal proangiogenic effect on mouse ischemic hindlimb. Stem Cell Res. Ther. 11, 162 (2020).10.1186/s13287-020-01669-9 ↗
8. Zou, Y. et al. SIRT6 inhibition delays peripheral nerve recovery by suppressing migration phagocytosis AND M2-polarization of macrophages. Cell Biosci. 11, 210 (2021).10.1186/s13578-021-00725-y ↗
9. Oshima, E. et al. M2 macrophage-derived cathepsin S promotes peripheral nerve regeneration via fibroblast–Schwann cell-signaling relay. J. Neuroinflamm. 20, 258 (2023).10.1186/s12974-023-02943-2 ↗
10. Yang, P. et al. Bionic peptide scaffold in situ polarization and recruitment of M2 macrophages to promote peripheral nerve regeneration. Bioact. Mater. 30, 85–97 (2023).
11. Bouchareychas, L. et al. Macrophage exosomes resolve atherosclerosis by regulating hematopoiesis AND inflammation via microRNA Cargo. Cell Rep. 32, 107881 (2020).10.1016/j.celrep.2020.107881 ↗
12. Liang, Y., Duan, L., Lu, J. & Xia, J. Engineering exosomes for targeted drug delivery. Theranostics 11, 3183–3195 (2021).10.7150/thno.52570 ↗
13. Locati, M., Curtale, G. & Mantovani, A. Diversity, mechanisms, and significance of macrophage plasticity. Annu. Rev. Pathol.: Mechanisms Dis. 15, 123–147 (2020).10.1146/annurev-pathmechdis-012418-012718 ↗
14. Huang, Q. et al. Aligned graphene mesh-supported double network natural hydrogel conduit loaded with netrin-1 for peripheral nerve regeneration. ACS Appl. Mater. Interfaces 13, 112–122 (2021).10.1021/acsami.0c16391 ↗
15. Yu, J., Liao, S. & Luo, Y. Netrin-1 in Post-stroke Neuroprotection: Beyond Axon Guidance Cue. Curr. Neuropharmacol. 20, 1879–1887 (2022).10.2174/1570159X20666220302150723 ↗
16. Jiang, Y. et al. Netrin1-Enriched Exosomes From Genetically Modified ADSCs as a Novel Treatment for Diabetic Limb Ischemia. Adv. Health. Mater. 14, e2403521 (2025).10.1002/adhm.202403521 ↗
17. Zhang, M. et al. Injectable Supramolecular Hybrid Hydrogel Delivers IL-1β-Stimulated Exosomes to Target Neuroinflammation. ACS Appl. Mater. Interfaces 15, 6486–6498 (2023).10.1021/acsami.2c19997 ↗
18. Yang, Q. et al. Novel injectable adhesive hydrogel loaded with exosomes for holistic repair of hemophilic articular cartilage defect. Bioact. Mater. 42, 85–111 (2024).
19. Yang, J. et al. Injectable carboxymethyl chitosan/konjac glucomannan/catechin hydrogel with free radical-scavenging antimicrobial AND pro-healing abilities for infected wound repair. Int. J. Biol. Macromol. 308, 142572 (2025).10.1016/j.ijbiomac.2025.142572 ↗
20. Feng, X. et al. Berberine in Cardiovascular and Metabolic Diseases: From Mechanisms to Therapeutics. Theranostics 9, 1923–1951 (2019).10.7150/thno.30787 ↗
21. Rashki, S. et al. Chitosan-based nanoparticles against bacterial infections. Carbohydr. Polym. 251, 117108 (2021).10.1016/j.carbpol.2020.117108 ↗
22. Kong, B. et al. Natural biopolymers derived hydrogels with injectable, self-healing, and tissue adhesive abilities for wound healing. Nano Res. 16, 2798–2807 (2023).10.1007/s12274-022-4936-8 ↗
23. Wang, J. et al. AAV-delivered suppressor tRNA overcomes a nonsense mutation in mice. Nature 604, 343–348 (2022).10.1038/s41586-022-04533-3 ↗
24. Liu, C. et al. A Redox Homeostasis Modulatory Hydrogel with GLRX3(+) Extracellular Vesicles Attenuates Disc Degeneration by Suppressing Nucleus Pulposus Cell Senescence. ACS Nano 17, 13441–13460 (2023).10.1021/acsnano.3c01713 ↗
25. Xu, H. et al. Bioactive glass-elicited stem cell-derived extracellular vesicles regulate M2 macrophage polarization and angiogenesis to improve tendon regeneration and functional recovery. Biomaterials 294, 121998 (2023).10.1016/j.biomaterials.2023.121998 ↗
26. Xu, W. et al. Injectable hydrogel encapsulated with VEGF-mimetic peptide-loaded nanoliposomes promotes peripheral nerve repair in vivo. Acta Biomater. 160, 225–238 (2023).10.1016/j.actbio.2023.02.004 ↗
27. Cattin, A. L. et al. Macrophage-Induced Blood Vessels Guide Schwann Cell-Mediated Regeneration of Peripheral Nerves. Cell 162, 1127–1139 (2015).10.1016/j.cell.2015.07.021 ↗
28. Ju, J., Liu, Y., Liang, H. & Yang, B. The role of pyroptosis in endothelial dysfunction induced by diseases. Front Immunol. 13, 1093985 (2022).10.3389/fimmu.2022.1093985 ↗
29. Zhu, M. et al. Crosstalk Between RPE Cells and Choroidal Endothelial Cells via the ANXA1/FPR2/SHP2/NLRP3 Inflammasome/Pyroptosis Axis Promotes Choroidal Neovascularization. Inflammation 45, 414–427 (2022).10.1007/s10753-021-01555-3 ↗
30. Hu, Q. et al. Hydrogen sulfide attenuates uranium-induced kidney cells pyroptosis via upregulation of PI3K/AKT/mTOR signaling. J. Biochem Mol. Toxicol. 37, e23220 (2023).10.1002/jbt.23220 ↗
31. Boyé, K. et al. Endothelial Unc5B controls blood-brain barrier integrity. Nat. Commun. 13, 1169 (2022).10.1038/s41467-022-28785-9 ↗
32. Hou, J. et al. Aerogel library with varying porous structures and mechanics regulates motor neuron progenitor differentiation for spinal cord injury repair. Mater. Today Bio. 35, 102404 (2025).10.1016/j.mtbio.2025.102404 ↗
33. Xu, Z. et al. Soft substrates promote direct chemical reprogramming of fibroblasts into neurons. Acta Biomater. 152, 255–272 (2022).10.1016/j.actbio.2022.08.049 ↗
34. Cheng, X., Xu, B., Lei, B. & Wang, S. Opposite Mechanical Preference of Bone/Nerve Regeneration in 3D-Printed Bioelastomeric Scaffolds/Conduits Consistently Correlated with YAP-Mediated Stem Cell Osteo/Neuro-Genesis. Adv. Healthc. Mater. 13, e2301158 (2024).10.1002/adhm.202301158 ↗
35. Wu, P. et al. Comprehensive strategy of conduit guidance combined with VEGF producing Schwann cells accelerates peripheral nerve repair. Bioact. Mater. 6, 3515–3527 (2021).
36. Dong, X. et al. An injectable and adaptable hydrogen sulfide delivery system for modulating neuroregenerative microenvironment. Sci. Adv. 9, eadi1078 (2023).10.1126/sciadv.adi1078 ↗
37. Alkazemi, H. et al. Spontaneous Orthogonal Alignment of Smooth Muscle Cells and Endothelial Cells Captures Native Blood Vessel Morphology in Tissue-Engineered Vascular Grafts. ACS Appl. Mater. Interfaces 15, 34631–34641 (2023).10.1021/acsami.3c08511 ↗
38. Jessen, K. R. & Arthur-Farraj, P. Repair Schwann cell update: Adaptive reprogramming, EMT, and stemness in regenerating nerves. Glia 67, 421–437 (2019).10.1002/glia.23532 ↗
39. Liu, B. et al. Myelin sheath structure and regeneration in peripheral nerve injury repair. Proc. Natl. Acad. Sci. USA 116, 22347–22352 (2019).10.1073/pnas.1910292116 ↗
40. Lund et al. CD163+ macrophages monitor enhanced permeability at the blood-dorsal root ganglion barrier. J. Exp. Med. 221, e20230675 (2024).10.1084/jem.20230675 ↗
41. Wang, J. Y. et al. Remodeling of the intra-conduit inflammatory microenvironment to improve peripheral nerve regeneration with a neuromechanical matching protein-based conduit. Adv. Sci. (Weinh.) 11, e2302988 (2024).
42. Xuan, Y. et al. Bredigite-based bioactive nerve guidance conduit for pro-healing macrophage polarization and peripheral nerve regeneration. Adv. Health. Mater. 13, e2302994 (2024).10.1002/adhm.202302994 ↗
43. Su, H. et al. A self-assembling peptide-based hydrogel containing NF-κB inhibitors and NGF for peripheral nerve injury repair. Biofabrication 17, https://doi.org/10.1088/1758-5090/adc340 (2025).10.1088/1758-5090/adc340 ↗
44. Fang, Z. et al. Enhancement of sciatic nerve regeneration with dual delivery of vascular endothelial growth factor and nerve growth factor genes. J. Nanobiotechnol. 18, 46 (2020).10.1186/s12951-020-00606-5 ↗
45. Qu, S. et al. Human adipose-derived stem cells delay muscular atrophy after peripheral nerve injury in rats. Cell Biochem. Biophys. 80, 555–562 (2022).10.1007/s12013-022-01082-4 ↗
46. Zhang, Y. et al. Tuina alleviates the muscle atrophy induced by sciatic nerve injury in rats through regulation of PI3K/Akt signaling. J. Orthop. Surg. Res. 19, 892 (2024).10.1186/s13018-024-05270-1 ↗
47. Cao, M. et al. Ginseng-derived nanoparticles alter macrophage polarization to inhibit melanoma growth. J. Immunother. Cancer 7, 326 (2019).10.1186/s40425-019-0817-4 ↗
48. Zhang, X. et al. Exosomes derived from adipose-derived stem cells overexpressing glyoxalase-1 protect endothelial cells and enhance angiogenesis in type 2 diabetic mice with limb ischemia. Stem Cell Res. Ther. 12, 403 (2021).10.1186/s13287-021-02475-7 ↗