{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T00:49:12Z","timestamp":1755218952643,"version":"3.43.0"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T00:00:00Z","timestamp":1754438400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Trigeminal neuralgia (TN), a debilitating neuropathic pain disorder, is characterized by demyelination and neuroinflammation, with limited therapies addressing its underlying pathophysiology. Bone Morphogenetic Protein 4 (BMP4) signaling and chemokine CCL5 are implicated in neuroinflammation and oligodendrocyte dysfunction, presenting potential therapeutic targets.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Peptide nanomicelles loaded with the BMP4 inhibitor DMH1 (NM@DMH1) were synthesized and characterized for stability, drug release kinetics, and biocompatibility. <jats:italic>In vitro<\/jats:italic> studies assessed oligodendrocyte progenitor cell (OPC) differentiation and anti-inflammatory effects in lipopolysaccharide-induced models. A rat TN model (chronic infraorbital nerve compression) evaluated NM@DMH1\u2019s efficacy in alleviating mechanical allodynia, demyelination, and neuroinflammation. Mechanistic roles of CCL5 were explored using recombinant protein supplementation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>NM@DMH1 exhibited uniform nanostructure (120\u00a0nm), high encapsulation efficiency (82%), and pH-responsive sustained release. Treatment enhanced OPC differentiation, reduced pro-inflammatory cytokines (IL-6, TNF-\u03b1, IL-1\u03b2), and suppressed CCL5 expression <jats:italic>in vitro<\/jats:italic>. In TN rats, NM@DMH1 significantly attenuated mechanical pain hypersensitivity (p &amp;lt; 0.01 vs model), restored myelin markers (MBP, MOG), and inhibited neuroinflammatory infiltration. CCL5 supplementation reversed therapeutic benefits, confirming its pivotal role.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>NM@DMH1 represents a nanotechnology-driven strategy targeting TN pathogenesis by promoting remyelination and suppressing CCL5-mediated neuroinflammation. This study advances precision drug delivery for neuropathic pain and highlights CCL5 as a novel therapeutic node, offering translational potential for TN and related neuroinflammatory disorders.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1590624","type":"journal-article","created":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T14:06:25Z","timestamp":1754489185000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["DMH1-loaded peptide nanomicelles restore myelin and attenuate neuroinflammation in trigeminal neuralgia via CCL5 suppression"],"prefix":"10.3389","volume":"16","author":[{"given":"Shuangyin","family":"Xia","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiunan","family":"Qin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaping","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"552","DOI":"10.4049\/jimmunol.166.1.552","article-title":"The chemokine RANTES is a crucial mediator of the progression from acute to chronic colitis in the rat","volume":"166","author":"Ajuebor","year":"2001","journal-title":"J. Immunol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"109","DOI":"10.2174\/1570159x17666191010094350","article-title":"Trigeminal neuralgia: basic and clinical aspects","volume":"18","author":"Araya","year":"2020","journal-title":"Curr. Neuropharmacol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1186\/s12903-020-01227-y","article-title":"Clinical characteristics and associated factors of trigeminal neuralgia: experience from addis Ababa, Ethiopia","volume":"20","author":"Ayele","year":"2020","journal-title":"BMC Oral Health"},{"key":"B4","doi-asserted-by":"publisher","first-page":"2650","DOI":"10.4049\/jimmunol.164.5.2650","article-title":"Role of CC chemokines (macrophage inflammatory Protein-1\u03b2, monocyte chemoattractant Protein-1, RANTES) in acute lung injury in rats","volume":"164","author":"Bless","year":"2000","journal-title":"J. Immunol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1049\/nbt2.12018","article-title":"Nanomicelles: types, properties and applications in drug delivery","volume":"15","author":"Bose","year":"2021","journal-title":"IET Nanobiotechnology"},{"key":"B6","doi-asserted-by":"publisher","first-page":"586","DOI":"10.1161\/hs0202.103399","article-title":"Flow cytometric analysis of inflammatory cells in ischemic rat brain","volume":"33","author":"Campanella","year":"2002","journal-title":"Stroke"},{"key":"B7","doi-asserted-by":"publisher","first-page":"115565","DOI":"10.1016\/j.bone.2020.115565","article-title":"Supramolecular self-assembling peptides to deliver bone morphogenetic proteins for skeletal regeneration","volume":"141","author":"Chen","year":"2020","journal-title":"Bone"},{"key":"B8","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1186\/s10194-023-01681-3","article-title":"BMP7 alleviates trigeminal neuralgia by reducing oligodendrocyte apoptosis and demyelination","volume":"24","author":"Chen","year":"2023","journal-title":"J. Headache Pain"},{"key":"B9","doi-asserted-by":"publisher","first-page":"836","DOI":"10.1016\/j.bbi.2024.05.007","article-title":"Bone morphogenetic protein 4 derived from the cerebrospinal fluid in patients with postherpetic neuralgia induces allodynia via the crosstalk between microglia and astrocyte","volume":"119","author":"Chen","year":"2024","journal-title":"Brain, Behav. Immun."},{"key":"B10","doi-asserted-by":"publisher","first-page":"14973","DOI":"10.1523\/jneurosci.1156-14.2014","article-title":"Migration of oligodendrocyte progenitor cells is controlled by transforming growth factor \u03b2 family proteins during corticogenesis","volume":"34","author":"Choe","year":"2014","journal-title":"J. Neurosci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"66","DOI":"10.3390\/antibiotics14010066","article-title":"Comparative structural and biophysical investigation of Lycosa erythrognatha toxin I (lyeTx I) and its analog LyeTx I-b","volume":"14","author":"de Souza","year":"2025","journal-title":"Antibiotics"},{"key":"B12","doi-asserted-by":"publisher","first-page":"201","DOI":"10.3892\/ijmm.2020.4593","article-title":"XPD inhibits cell growth and invasion and enhances chemosensitivity in esophageal squamous cell carcinoma by regulating the PI3K\/AKT signaling pathway","volume":"46","author":"Jian","year":"2020","journal-title":"Int. J. Mol. Med."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1434","DOI":"10.1097\/j.pain.0000000000002156","article-title":"G protein\u2013coupled receptor GPR151 is involved in trigeminal neuropathic pain through the induction of G\u03b2\u03b3\/extracellular signal-regulated kinase-mediated neuroinflammation in the trigeminal ganglion","volume":"162","author":"Jiang","year":"2020","journal-title":"Pain"},{"key":"B14","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1007\/s11916-019-0810-0","article-title":"A comprehensive review of trigeminal neuralgia","volume":"23","author":"Jones","year":"2019","journal-title":"Curr. Pain Headache Rep."},{"key":"B15","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1007\/s11916-024-01227-5","article-title":"Recent advances in management of neuropathic, nociceptive, and chronic pain: a narrative review with focus on nanomedicine, gene therapy, stem cell therapy, and newer therapeutic options","volume":"28","author":"Kataria","year":"2024","journal-title":"Curr. Pain Headache Rep."},{"key":"B16","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1038\/hr.2015.62","article-title":"CCL5 upregulates IL-10 expression and partially mediates the antihypertensive effects of IL-10 in the vascular smooth muscle cells of spontaneously hypertensive rats","volume":"38","author":"Kim","year":"2015","journal-title":"Hypertens. Res."},{"key":"B17","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1136\/practneurol-2020-002782","article-title":"Trigeminal neuralgia: a practical guide","volume":"21","author":"Lambru","year":"2021","journal-title":"Pract. Neurol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1283","DOI":"10.1016\/j.pain.2012.03.008","article-title":"Absence of C\u2013C motif chemokine ligand 5 in mice leads to decreased local macrophage recruitment and behavioral hypersensitivity in a murine neuropathic pain model","volume":"153","author":"Liou","year":"2012","journal-title":"Pain"},{"key":"B19","doi-asserted-by":"publisher","first-page":"18111","DOI":"10.1038\/s41598-023-44013-w","article-title":"Attenuates reactive oxygen species: induced pyroptosis via activation of the Nrf2\/HO-1 signal pathway in models of trigeminal neuralgia","volume":"13","author":"Liu","year":"2023","journal-title":"Sci. Rep."},{"key":"B20","doi-asserted-by":"publisher","first-page":"2347","DOI":"10.1093\/brain\/124.12.2347","article-title":"Trigeminal neuralgia: pathology and pathogenesis","volume":"124","author":"Love","year":"2001","journal-title":"Brain"},{"key":"B21","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1093\/procel\/pwae015","article-title":"Engineered extracellular vesicles enable high-efficient delivery of intracellular therapeutic proteins","volume":"15","author":"Ma","year":"2024","journal-title":"Protein. Cell."},{"key":"B22","doi-asserted-by":"publisher","first-page":"6253","DOI":"10.2147\/ijn.s498012","article-title":"Tolvaptan-loaded tomato-derived nanovesicles: characterization and evaluation of cytotoxicity, wound healing potential and the effects on cyst formation in renal cell lines","volume":"20","author":"Mammadova","year":"2025","journal-title":"IJN"},{"key":"B23","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1177\/204946371100500105","article-title":"Trigeminal neuralgia\u2014A debilitating facial pain","volume":"5","author":"McMillan","year":"2011","journal-title":"Rev. Pain"},{"key":"B24","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1165\/rcmb.2013-0086ma","article-title":"Flow cytometric analysis of macrophages and dendritic cell subsets in the mouse lung","volume":"49","author":"Misharin","year":"2013","journal-title":"Am. J. Respir. Cell. Mol. Biol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"e1117","DOI":"10.1097\/pr9.0000000000001117","article-title":"Heightened presence of inflammatory mediators in the cerebrospinal fluid of patients with trigeminal neuralgia","volume":"8","author":"Ostertag","year":"2023","journal-title":"PR9"},{"key":"B26","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1186\/s12951-018-0392-8","article-title":"Nano based drug delivery systems: recent developments and future prospects","volume":"16","author":"Patra","year":"2018","journal-title":"J. Nanobiotechnol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"781310","DOI":"10.3389\/fimmu.2021.781310","article-title":"Blockade of CC chemokine receptor type 3 diminishes pain and enhances opioid analgesic potency in a model of neuropathic pain","volume":"12","author":"Pawlik","year":"2021","journal-title":"Front. Immunol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"4855","DOI":"10.2174\/0929867326666190712154021","article-title":"Self-assembling peptides in current nanomedicine: versatile nanomaterials for drug delivery","volume":"27","author":"Peng","year":"2020","journal-title":"CMC"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1079","DOI":"10.3389\/fimmu.2017.01079","article-title":"CCL5\u2013Glutamate cross-talk in astrocyte-neuron communication in multiple sclerosis","volume":"8","author":"Pittaluga","year":"2017","journal-title":"Front. Immunol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"747463","DOI":"10.3389\/fsurg.2021.747463","article-title":"Characteristics of patients with trigeminal neuralgia referred to the Indonesian national brain center neurosurgery clinic","volume":"8","author":"Prasetya","year":"2022","journal-title":"Front. Surg."},{"key":"B31","doi-asserted-by":"publisher","first-page":"e008145","DOI":"10.1136\/jitc-2023-008145","article-title":"Development of therapeutic monoclonal antibodies against DKK1 peptide-HLA-A2 complex to treat human cancers","volume":"12","author":"Qian","year":"2024","journal-title":"J. Immunother. Cancer"},{"key":"B32","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1186\/s12989-023-00529-7","article-title":"Uncovering the fate and risks of intravenously injected prussian blue nanoparticles in mice by an integrated methodology of toxicology, pharmacokinetics, proteomics, and metabolomics","volume":"20","author":"Qu","year":"2023","journal-title":"Part Fibre Toxicol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"2586","DOI":"10.1021\/bm800462q","article-title":"Facile preparation of well-defined AB2 Y-Shaped miktoarm star polypeptide copolymer via the combination of ring-opening polymerization and click chemistry","volume":"9","author":"Rao","year":"2008","journal-title":"Biomacromolecules"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1314","DOI":"10.1007\/s12264-021-00696-7","article-title":"Pinocembrin promotes OPC differentiation and remyelination via the mTOR signaling pathway","volume":"37","author":"Shao","year":"2021","journal-title":"Neurosci. Bull."},{"key":"B35","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/bs.pbr.2019.03.013","article-title":"Oligodendrocyte precursor cells as a therapeutic target for demyelinating diseases","volume":"245","author":"Skaper","year":"2019","journal-title":"Prog. Brain Res."},{"key":"B36","doi-asserted-by":"publisher","first-page":"105","DOI":"10.3390\/gels11020105","article-title":"Ophthalmic in situ nanocomposite gel for delivery of a hydrophobic antioxidant","volume":"11","author":"Slavkova","year":"2025","journal-title":"Gels"},{"key":"B37","doi-asserted-by":"publisher","first-page":"2330","DOI":"10.3390\/life13122330","article-title":"Agaricus bisporus-derived glucosamine hydrochloride regulates VEGF through BMP signaling to promote zebrafish vascular development and impairment repair","volume":"13","author":"Sun","year":"2023","journal-title":"Life"},{"key":"B38","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1016\/j.msec.2016.02.007","article-title":"Comb-like amphiphilic polypeptide-based copolymer nanomicelles for co-delivery of doxorubicin and P-gp siRNA into MCF-7 cells","volume":"62","author":"Suo","year":"2016","journal-title":"Mater. Sci. Eng. C"},{"key":"B39","doi-asserted-by":"publisher","first-page":"85","DOI":"10.3892\/mmr.2022.12601","article-title":"RGMa regulates CCL5 expression via the BMP receptor in experimental autoimmune encephalomyelitis mice and endothelial cells","volume":"25","author":"Tang","year":"2022","journal-title":"Mol. Med. Rep."},{"key":"B40","doi-asserted-by":"publisher","first-page":"70","DOI":"10.3390\/nano11010070","article-title":"Recent advances in nanomicelles delivery systems","volume":"11","author":"Tawfik","year":"2020","journal-title":"Nanomaterials"},{"key":"B41","doi-asserted-by":"publisher","first-page":"82","DOI":"10.3390\/pharmaceutics10030082","article-title":"Buspirone nanovesicular nasal system for non-hormonal hot flushes treatment","volume":"10","author":"Touitou","year":"2018","journal-title":"Pharmaceutics"},{"key":"B42","doi-asserted-by":"publisher","first-page":"eadn9980","DOI":"10.1126\/scitranslmed.adn9980","article-title":"Oligodendroglial precursor cells modulate immune response and early demyelination in a murine model of multiple sclerosis","volume":"17","author":"Wang","year":"2025","journal-title":"Sci. Transl. Med."},{"key":"B43","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1007\/s40820-024-01443-z","article-title":"Toward artificial peptide nanocapsules","volume":"16","author":"Wang","year":"2024","journal-title":"Nano-Micro Lett."},{"key":"B44","doi-asserted-by":"publisher","first-page":"e14642","DOI":"10.1111\/cns.14642","article-title":"Acetyl-11-keto-beta-boswellic acid modulates macrophage polarization and schwann cell migration to accelerate spinal cord injury repair in rats","volume":"30","author":"Wang","year":"2024","journal-title":"CNS Neurosci. Ther."},{"key":"B45","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1186\/s13578-020-00456-6","article-title":"Nrf2 promotes esophageal squamous cell carcinoma (ESCC) resistance to radiotherapy through the CaMKII\u03b1-associated activation of autophagy","volume":"10","author":"Xia","year":"2020","journal-title":"Cell. Biosci."},{"key":"B46","doi-asserted-by":"publisher","first-page":"1744806919892100","DOI":"10.1177\/1744806919892100","article-title":"Role of bone morphogenetic protein-2\/4 in astrocyte activation in neuropathic pain","volume":"15","author":"Yang","year":"2019","journal-title":"Mol. Pain"},{"key":"B47","doi-asserted-by":"publisher","first-page":"e110","DOI":"10.1097\/scs.0000000000005879","article-title":"Relationship of inflammation with trigeminal neuralgia","volume":"31","author":"Yao","year":"2020","journal-title":"J. Craniofacial Surg."},{"key":"B48","doi-asserted-by":"publisher","first-page":"3551","DOI":"10.1016\/j.biomaterials.2009.03.024","article-title":"Incorporation of a sequential BMP-2\/BMP-7 delivery system into chitosan-based scaffolds for bone tissue engineering","volume":"30","author":"Yilgor","year":"2009","journal-title":"Biomaterials"},{"key":"B49","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1097\/00002508-200201000-00003","article-title":"Diagnosis and differential diagnosis of trigeminal neuralgia","volume":"18","author":"Zakrzewska","year":"2002","journal-title":"Clin. J. Pain"},{"key":"B50","doi-asserted-by":"publisher","first-page":"112820","DOI":"10.1016\/j.expneurol.2018.09.003","article-title":"Localised non-viral delivery of nucleic acids for nerve regeneration in injured nervous systems","volume":"319","author":"Zhang","year":"2019","journal-title":"Exp. Neurol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"7660118","DOI":"10.1155\/2022\/7660118","article-title":"Autologous bioactive compound concentrated growth factor ameliorates fistula healing of anal fistula in a pig model and promotes proliferation and migration of human skin fibroblasts via regulating the MEK\/ERK pathway","volume":"2022","author":"Zhang","year":"2022","journal-title":"Oxidative Med. Cell. Longev."},{"key":"B52","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1038\/s41419-025-07666-1","article-title":"Cellular senescence promotes macrophage-to-myofibroblast transition in chronic ischemic renal disease","volume":"16","author":"Zhao","year":"2025","journal-title":"Cell. Death Dis."},{"key":"B53","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1007\/s11307-025-01993-7","article-title":"Dual targeting of Neuropilin-1 and glucose transporter for efficient fluorescence imaging of cancer","volume":"27","author":"Zhu","year":"2025","journal-title":"Mol. Imaging Biol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1186\/s13024-024-00742-8","article-title":"The interplay of inflammation and remyelination: rethinking MS treatment with a focus on oligodendrocyte progenitor cells","volume":"19","author":"Zveik","year":"2024","journal-title":"Mol. Neurodegener."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1590624\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T14:06:27Z","timestamp":1754489187000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1590624\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,6]]},"references-count":54,"alternative-id":["10.3389\/fphar.2025.1590624"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1590624","relation":{},"ISSN":["1663-9812"],"issn-type":[{"type":"electronic","value":"1663-9812"}],"subject":[],"published":{"date-parts":[[2025,8,6]]},"article-number":"1590624"}}