Nose-to-Brain Nanocarriers for Migraine Management: A Comprehensive Review of Drug Delivery Strategies and Translational Challenges

Abstract

Migraine is among the most prevalent neurological disorders and can affect people’s daily activities because of high- and long-lasting pain intensity attacks. The available dosage forms, such as oral and parenteral formulations, can enhance patients’ symptoms but still have poor side effects, bioavailability, or dosing difficulty. As a result, there is an urgent need to find other novel drug delivery systems (DDSs) to treat migraine. The intranasal (IN) route was investigated as an alternative pathway to deliver therapeutic molecules directly to the brain, bypassing the blood–brain barrier (BBB) and hepatic first-pass metabolism. Nanocarriers facilitate drug transportation regardless of their lipophilicity, resulting in more efficient drug absorption and bioavailability. They also effectively contribute to brain targeting, which maximizes the therapeutic effect of drugs. This review discusses the efficacy of nanocarriers loaded with antimigraine agents and delivered by the IN route in the management of migraine. In preclinical studies, nanocarriers such as liposomes, ethosomes, nanostructured lipid carriers, and many others have been used to enhance brain targeting. Studies have focused on obtaining high results for brain pharmacokinetics, such as drug targeting efficiency (DTE) and direct transport percentage (DTP). This leads to better drug accumulation and a rapid onset of action. Despite the proven success of preclinical studies on the delivery of migraine drugs loaded with nanocarriers through the IN route, there is still a shortage in translating this success into the clinical stage.

Keywords

Migraine / Nose-to-brain delivery / Lipid nanocarriers / Intranasal administration / Preclinical pharmacokinetics / Brain targeting / Drug delivery systems

References

[1] Virmani R, Virmani T, Pathak K. Nanovesicles for delivery of central nervous system drugs. Applications of Nanovesicular Drug Delivery. Amsterdam: Elsevier; 2022:315–339.

[2] Anusha SV, Ratna J, Swarnalatha S, et al.. Brain targeting through intranasal route: an overview. J Pharm Res Int., 2021, 33: 112-124

[3] Kaur K, Hernandez V, Al Hajaj SW, et al.. The efficacy of herbal supplements and nutraceuticals for prevention of migraine: can they help?. Cureus., 2021, 13(5e14868

[4] Assadpour S, Shiran MR, Akhtari J. Chitosan coating of anionic liposomes containing sumatriptan succinate: a candidate for nasal administration. 2021.

[5] Mathure D, Sutar AD, Ranpise H, et al.. Preparation and optimization of liposome containing ThermosensitiveIn SituNasal hydrogel system for brain delivery of sumatriptan succinate. ASSAY Drug Dev Technol., 2023, 21(1): 3-16

[6] Mura P, Maestrelli F, Cirri M, et al.. Multiple roles of chitosan in mucosal drug delivery: an updated review. Mar Drugs., 2022, 20(5): 335

[7] de Barros C, Portugal I, Batain F, et al.. Formulation, design and strategies for efficient nanotechnology-based nasal delivery systems. RPS Pharm Pharmacol Rep, 2022, 1: rqac003

[8] Vitorino C, Jorge A, Pais A. Recent trends in nanotechnology for brain delivery: a brief outlook, 2021, Nanoparticles for Brain Drug Delivery, Jenny Stanford Publishing3-7

[9] Schwinghammer TL, DiPiro JT, Ellingrod VL, et al. Pharmacotherapy handbook. McGraw Hill; 2021.

[10] Levin MLevin M. International classification of headache disorders and diagnosis of migraine and its subtypes. Comprehensive review of headache medicine, 2025, Oxford, Oxford University Press101-114

[11] Narimani MG, Kalalinia F, Marouzi S, et al.. Nanoformulation innovations: Revolutionizing precision in migraine therapy. Iran J Basic Med Sci., 2025, 28(1): 16

[12] Assadpour S, Akhtari J, Shiran MR. Pharmacokinetics study of chitosan-coated liposomes containing sumatriptan in the treatment of migraine. Casp J Int Med., 2022, 13(1): 90

[13] Ashraf U, Goadsby PJ. Migraine: advances in treatment. Trends Mol Med., 2026, 32(4): 385-398

[14] Puledda F, Silva EM, Suwanlaong K, et al.. Migraine: from pathophysiology to treatment. J Neurol., 2023, 270(7): 3654-3666

[15] Haanes KA, Edvinsson L. Molecular and cellular mechanisms of CGRP antagonists. Novel Synthetic Drugs in Migraine. Cham: Springer International Publishing,; 2022:19–31.

[16] Balcziak LK, Russo AF. Dural immune cells, CGRP, and migraine. Front Neurol., 2022, 13 ArticleID: 874193

[17] Alexander A, Agrawal M, Bhupal Chougule M, et al. Nose-to-brain drug delivery. Nanopharmaceuticals. Amsterdam: Elsevier; 2020:175–200.

[18] Silvestro M, Iannone LF, Orologio I, et al.. Migraine treatment: towards new pharmacological targets. Int J Mol Sci., 2023, 24(15): 12268

[19] Rivera-Mancilla E, MaassenVanDenBrink A. Novel pharmacological targets of migraine: an overview. Novel Synthetic Drugs in Migraine. Cham: Springer International Publishing. 2022:1–17.

[20] Waliszewska-Prosół M, Raffaelli B, Straburzyński M, et al.. Understanding the efficacy and tolerability of migraine treatment: a deep dive into CGRP antagonists. Expert Rev Clin Pharmacol., 2024, 17(11): 1039-1051

[21] Tanaka M, Szabó Á, Körtési T, et al.. From CGRP to PACAP, VIP, and beyond: unraveling the next chapters in migraine treatment. Cells., 2023, 12(22): 2649

[22] Messina R, Huessler EM, Puledda F, et al.. Safety and tolerability of monoclonal antibodies targeting the CGRP pathway and gepants in migraine prevention: a systematic review and network meta-analysis. Cephalalgia., 2023, 43(3): 03331024231152169

[23] Jakubowska B, Sowa-Kućma M. Gepants: targeting the CGRP pathway for migraine relief. Front Pharmacol., 2025, 16: 1708226

[24] Gebril A, Obeid MA, Bennett EM, et al.. Mucosal and systemic immune responses following mucosal immunisation of tetanus toxoid entrapped in lipid nanoparticles prepared by microwave reactor. Eur J Pharm Biopharm., 2022, 171: 11-18

[25] Martin V, Hoekman J, Aurora SK, et al.. Nasal delivery of acute medications for migraine: the upper versus lower nasal space. J Clin Med., 2021, 10(11): 2468

[26] Assadpour S, Shiran MR, Asadi P, et al.. Harnessing intranasal delivery systems of sumatriptan for the treatment of migraine. BioMed Res Int., 2022, 2022: 3692065

[27] Li G, Duan S, Zhu T, et al.. Efficacy and safety of intranasal agents for the acute treatment of migraine: a systematic review and network meta-analysis. J Headache Pain., 2023, 24(1): 129

[28] Khan AA, Qayyum SN, Ghaddar SA. Migraine management: assessing the potential of newly FDA-approved Zavzpret nasal spray as first-line therapy. Int J Surg Glob Health., 2024, 7(2e0314

[29] Dhillon S. Zavegepant: first approval. Drugs., 2023, 83(9): 825-831

[30] Fan H, Wadolowski J, Shan R, et al.. Clinical evaluation of zavegepant for the acute treatment of migraine. J Manag Care Specialty Pharm., 2025, 31(6): 598-602

[31] Zhu Z, Tang Y, Li L, et al.. The efficacy and safety of zavegepant nasal inhalation versus oral calcitonin-gene related peptide receptor antagonists in the acute treatment of migraine: a systematic review and network meta-analysis of the literature. J Headache Pain., 2025, 26(1): 48

[32] Devadoss T, Pingili RB. Drugs under clinical trials for the treatment of migraine. Management of Migraine Pain. Singapore: Springer Nature Singapore 2024:229–249.

[33] Multicenter, randomized, double-blind, placebo-controlled, dose-ranging Phase II trial of PRT-064040 nasal spray for the acute treatment of migraine [Internet]. Bethesda (MD): National Library of Medicine (US); 2025. Available from: https://clinicaltrials.gov/study/NCT07304518. Identifier: NCT07304518.

[34] Aljabali AAA, Alzoubi L, Hamzat Y, et al.. A potential MRI agent and an anticancer drug encapsulated within CPMV virus-like particles. Comb Chem High Throughput Screen., 2021, 24(10): 1557-1571

[35] Keller LA, Merkel O, Popp A. Intranasal drug delivery: opportunities and toxicologic challenges during drug development. Drug Deliv Transl Res., 2022, 12(4): 735-757

[36] Kaur G, Goyal J, Behera PK, et al.. Unraveling the role of chitosan for nasal drug delivery systems: a review. Carbohydr Polym Technol Appl., 2023, 5100316

[37] Chattopadhyay S, Das S, Sarma KN. Nose-to-brain drug delivery: an update to the alternative path to successful targeted anti-migraine drugs. Int J App Pharm., 2021, 13: 67-75

[38] Martin GP, Lansley ABTaylor KMG, V ME. Nasal drug delivery. Aulton’s pharmaceutics: the design and manufacture of medicines, 20216Amsterdam, Elsevier

[39] Duong VA, Nguyen TTL, Maeng HJ. Recent advances in intranasal liposomes for drug, gene, and vaccine delivery. Pharmaceutics., 2023, 15(1): 207

[40] Khute S, Jangde RK. Optimization of nasal liposome formulation of venlafaxine hydrochloride using a box-behnken experimental design. Curr Ther Res., 2023, 99 ArticleID: 100714

[41] Pandey V, Gadeval A, Asati S, et al.Tekade RK, et al.. Formulation strategies for nose-to-brain delivery of therapeutic molecules. Drug delivery systems, 2021, Amsterdam, Elsevier291-332

[42] Formica ML, Real DA, Picchio ML, et al.. On a highway to the brain: a review on nose-to-brain drug delivery using nanoparticles. Appl Mater Today., 2022, 29 ArticleID: 101631

[43] Nguyen TTL, Duong VA. Advancements in nanocarrier systems for nose-to-brain drug delivery. Pharmaceuticals., 2025, 18(5): 615

[44] Aljabali AAA, Obeid MA. Inorganic-organic nanomaterials for therapeutics and molecular imaging applications. Nanosci Nanotechnol Asia., 2020, 10(6): 748-765

[45] Mohd Nordin UU, Ahmad N, Salim N, et al.. Lipid-based nanoparticles for psoriasis treatment: a review on conventional treatments, recent works, and future prospects. RSC Adv., 2021, 11(46): 29080-29101

[46] Lee D, Minko T. Nanotherapeutics for nose-to-brain drug delivery: an approach to bypass the blood brain barrier. Pharmaceutics., 2021, 13(12): 2049

[47] Padalkar RR, Madgulkar AR, Bhalekar MR. Brain targeted delivery of rizatriptan using glutathione conjugated liposomes through transmucosal nasal route. Int J Pharm Investig., 2020, 10(3): 344-350

[48] Obeid MA, Aljabali AAA, Rezigue M, et al.Hargadon KM, et al.. Use of nanoparticles in delivery of nucleic acids for melanoma treatment. Melanoma, 2021, New York, NY, Springer US591620

[49] Agiba AM, Arreola-Ramírez JL, Carbajal V, et al.. Light-responsive and dual-targeting liposomes: from mechanisms to targeting strategies. Molecules., 2024, 29(3): 636

[50] Chettupalli AK, Katta S, Fateh MV, et al.. Design, optimization, and characterization of Zolmitriptan loaded liposomal gels for intranasal delivery for acute migraine therapy. Intell Pharm., 2025, 3(1): 11-25

[51] Aljabali AA, Obeid MA, Amawi HA, et al. Application of nanomaterials in the diagnosis and treatment of genetic disorders. In: Applications of nanomaterials in human health. Singapore: Springer Singapore; 2020:125–146.

[52] Obeid MA, Alyamani H, Amawi H, et al.Hargadon KM, et al.. siRNA delivery to melanoma cells with cationic niosomes. Melanoma, 2021, New York, NY, Springer US621634

[53] Khunt D, Shah B, Lakhatariya M, et al. Lipid nanocrystals: an overview on formulation to clinical translation. In: Lipid-based drug delivery systems. New York: Jenny Stanford Publishing; 2023:125–146.

[54] Mo K, Kim A, Choe S, et al.. Overview of solid lipid nanoparticles in breast cancer therapy. Pharmaceutics., 2023, 15(8): 2065

[55] Dhande HS, Taksande JB, Awandekar NB, et al.. Pharmacodynamic and physicochemical evaluation of intranasal zolmitriptan-loaded nanostructured lipid carriers: for enhanced antimigraine potential. ASSAY Drug Dev Technol., 2025, 2025: 016

[56] Das M, Sarma A, Baruah H, et al.. Insight into central nervous system targeted nanostructured lipid carriers via the nose to brain pathway. RSC Pharm., 2024, 1(5): 904-927

[57] Alyamani H, Obeid MA, Tate RJ, et al.. Exosomes: fighting cancer with cancer. Ther Deliv., 2019, 10(1): 37-61

[58] Obeid MA, Haifawi S, Khadra I. The impact of solvent selection on the characteristics of niosome nanoparticles prepared by microfluidic mixing. Int J Pharm X., 2023, 5100168

[59] Modi C, Kanada K, Prajapati B, et al. Transfersomes as Transporters via Lipid-Based Drug Delivery System. In: Lipid-based drug delivery systems. Singapore: Jenny Stanford Publishing; 2023:185–212.

[60] Basu B, Dutta A, Parihar A, et al. Ethosomes: a lipid-based drug delivery system. In: Lipid-based drug delivery systems. Singapore: Jenny Stanford Publishing; 2023:223–297.

[61] Almuqbil RM, Aldhubiab B. Ethosome-based transdermal drug delivery: its structural components, preparation techniques, and therapeutic applications across metabolic, chronic, and oncological conditions. Pharmaceutics., 2025, 17(5): 583

[62] Zhan B, Wang J, Li H, et al.. Ethosomes: a promising drug delivery platform for transdermal application. Chemistry., 2024, 6(5): 993-1019

[63] Ezzaki C, Chaari A, Al-Othman A. Recent advances on chitosan-based nanoparticles for brain drug delivery. Polymers., 2025, 17(22): 3055

[64] Omidian H, Gill EJ, Dey Chowdhury S, et al.. Chitosan nanoparticles for intranasal drug delivery. Pharmaceutics., 2024, 16(6): 746

[65] Shinde AJ, Swami KB, Tamboli FA, et al.. Design and development of zolmitriptan niosomal in situ nasal gel for the treatment of migrain. Int J Res Pharm Sci., 2021, 12(3): 1861-1869

[66] Mehta FF, Patel J, Barot S. Development and evaluation of in-situ nasal gel formulations of nanosized transferosomal triptans. J Neon Surg, 2025, 14(7): 122-130

[67] Masjedi M, Azadi A, Heidari R, et al.. Nose-to-brain delivery of sumatriptan-loaded nanostructured lipid carriers: preparation, optimization, characterization and pharmacokinetic evaluation. J Pharm Pharmacol., 2020, 72(10): 1341-1351

[68] Castelino C, Arnold K. Chitosan nanoparticle intranasal delivery of sumatriptan succinate. 2024;6(1).

[69] Kempwade AA, Taranalli AD, Hiremath RD, et al.. Formulation and evaluation of flexible liposome embedded in situ thermoreversible intranasal gel of rizatriptan benzoate. Indian J Pharm Sci., 2022, 84(4): 863-873

[70] Mathure D, Ranpise H, Awasthi R, et al.. Formulation and characterization of nanostructured lipid carriers of rizatriptan benzoate-Loaded In Situ Nasal gel for brain targeting. ASSAY Drug Dev Technol., 2022, 20(5): 211-224

[71] Hamzah M, Kassab H. Formulation and characterization of intranasal drug delivery of frovatriptan-loaded binary ethosomes gel for brain targeting. Nanotechnol Sci Appl., 2024, 17: 1-19

[72] Whealy M, Becker WJ. The 5-HT_1B and 5-HT_1D agonists in acute migraine therapy: Ergotamine, dihydroergotamine, and the triptans. In: Migraine management. Amsterdam: Elsevier; 2024:17–42.

[73] Mitsikostas DD, Ward TN. Evidence-based symptomatic treatment of migraine Migraine Management. Amsterdam: Elsevier, 2024, 199: 203-218

[74] Kamourieh S, Rozen T, Anderson JMJHOCN. Status migrainosus. Handbook Clin Neurol, 2024, 199: 413-439

[75] Abu-Arafeh I, Howells R. Management of migraine in children and adolescents. Migraine Management. Amsterdam: Elsevier; 2024:487–502.

[76] Youssef NAHA, Kassem AA, Farid RM, et al.. A novel nasal almotriptan loaded solid lipid nanoparticles in mucoadhesive in situ gel formulation for brain targeting: Preparation, characterization and in vivo evaluation. Int J Pharm., 2018, 548(1): 609-624

[77] Rocha B, Rocha NP, Gago B. Translational challenges. In: Nanoparticles for brain drug delivery. Singapore: Jenny Stanford Publishing; 2021:453–471.

[78] Kumarasamy RV, Natarajan PM, Umapathy VR, et al.. Clinical applications and therapeutic potentials of advanced nanoparticles: a comprehensive review on completed human clinical trials. Front Nanotechnol., 2024, 6: 1479993

[79] Cai L, Xu H, Cui Z. Factors limiting the translatability of rodent model–based intranasal vaccine research to humans. AAPS PharmSciTech., 2022, 23(6): 191

[80] Stucki AO, Sauer UG, Allen DG, et al.. Differences in the anatomy and physiology of the human and rat respiratory tracts and impact on toxicological assessments. Regul Toxicol Pharmacol., 2024, 150 ArticleID: 105648

[81] Zheng S, Guo Y, Yan F, et al.. Chances and challenges in intranasal administration delivery for brain disease treatment. Clin Transl Discov., 2023, 3(6 ArticleID: e253

[82] Levine A, Vanderah TW, Largent-Milnes TM. An underrepresented majority: a systematic review utilizing allodynic criteria to examine the present scarcity of discrete animal models for episodic migraine. Cephalalgia., 2021, 41(3): 404-416

[83] Spekker E, Fejes-Szabó A, Nagy-Grócz G. Models of trigeminal activation: is there an animal model of migraine?. Brain Sci., 2024, 14(4): 317

[84] Dighe S, Jog S, Momin M, et al.. Intranasal drug delivery by nanotechnology: advances in and challenges for Alzheimer’s disease management. Pharmaceutics., 2024, 16(1): 58

[85] Gandhi S, Shastri DH, Shah J, et al.. Nasal delivery to the brain: harnessing nanoparticles for effective drug transport. Pharmaceutics., 2024, 16(4): 481

[86] Aljabali AAA, Rezigue M, Alsharedeh RH, et al.. Protein-based drug delivery nanomedicine platforms: recent developments. Pharm Nanotechnol., 2022, 10(4): 257-267

[87] Hejmady S, Singhvi G, Saha RN, et al.. Regulatory aspects in process development and scale-up of nanopharmaceuticals. Ther Deliv., 2020, 11(6): 341-343

[88] Stucchi F, Li M, Castellano G, et al.. Regulatory framework for polymer-based nanotherapeutics in clinical translation. Front Bioeng Biotechnol., 2026, 14: 1735885

[89] Aljabali AAA, Tambuwala MM, Obeid MA. Microfluidic manufacturing of niosomes. In: Microfluidics in pharmaceutical sciences. Cham: Springer Nature Switzerland; 2024:77–108.

[90] Hasan MM, Rahman MM, Kabir A, et al.. Contemporary investigation on nasal spray drug delivery system International. J Pharm Therap, 2016, 7(4): 184-200

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