Brain-derived Neurotrophic Factor and Its Applications through Nanosystem Delivery

Document Type : Review Paper


1 Department of Pharmacology, School of Pharmacy, Shandong University of Traditional Chinese Medicine, Ji’nan 250355, China.

2 Center for Foreign Language Translation, College of Foreign Languages, Shandong University of Traditional Chinese Medicine, Ji’nan250355, China.

3 Innovation Research Institute of Chinese Medicine, Shandong University of Traditional Chinese Medicine, Ji’nan 250355, China.

4 Department of Drug Design, College of Intelligence and Information Engineering, Shandong University of Traditional Chinese Medicine, Ji’nan 250355, China.

5 Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Ji’nan 250014, China.



Brain-derived neurotrophic factor (BDNF) is a protein that performs a neurotrophic function. BDNF and its receptors are widely expressed in the nervous system and can promote the growth of neurons and the formation of neuronal synapses in the brain. Studies have shown that a lack of BDNF can lead to impairment of memory and cognitive functions, indicating that BDNF plays an important role in mental illness and neurodegenerative diseases. The combination of stem cells and BDNF-releasing nanomaterials holds great promise in regenerative medicine, especially in the treatment of neurological diseases. For example, Alzheimer's disease, depression, Parkinson's disease, spinal cord injury, etc. The combination of stem cell/pharmacologically active carrier and BDNF-nano/hydrogel provided a useful new type of local delivery tool for the treatment of the nervous system and other diseases. It can not only provide BDNF but also stem cells. These studies will provide a scientific basis for the development and application of BDNF in the future.

Graphical Abstract

Brain-derived Neurotrophic Factor and Its Applications through Nanosystem Delivery


(1) Murer MG, Yan Q and Raisman-Vozari R. Brainderived neurotrophic factor in the control human
brain, and in Alzheimer’s disease and Parkinson’s
disease. Prog. Neurobiol. (2001) 63: 71-124.
(2) Tapia-Arancibia L, Aliaga E, Silhol M and
Arancibia S. New insights into brain BDNF
function in normal aging and Alzheimer disease.
Brain Res. Rev. (2008) 59: 201-20.
(3) Conner JM, Lauterborn JC, Yan Q, Gall CM and
Varon S. Distribution of brain-derived neurotrophic
factor (BDNF) protein and mRNA in the normal
adult rat CNS: evidence for anterograde axonal
transport. J. Neurosci. (1997) 17: 2295-313.
(4) Kerschensteiner M, Gallmeier E, Behrens L, Leal
VV, Misgeld T, Klinkert WE, Kolbeck R, Hoppe
E, Oropeza-Wekerle RL, Bartke I, Stadelmann C,
Lassmann H, Wekerle H and Hohlfeld R. Activated 
Xia M et al. / IJPR (2021), 20 (4): 137-151
human T cells, B cells, and monocytes produce
brain-derived neurotrophic factor in vitro and in
inflammatory brain lesions: a neuroprotective role
of inflammation? J. Exp. Med. (1999) 189: 865-70.
(5) Yarrow JF, White LJ, McCoy SC and Borst SE.
Training augments resistance exercise induced
elevation of circulating brain derived neurotrophic
factor (BDNF). Neurosci. Lett. (2010) 479: 161-5.
(6) Lu B, Nagappan G and Lu Y. BDNF and synaptic
plasticity, cognitive function, and dysfunction.
Handb. Exp. Pharmacol. (2014) 220: 223-50.
(7) Sasi M, Vignoli B, Canossa M and Blum R.
Neurobiology of local and intercellular BDNF
signaling. Pflug. Arch. Eur. J. Physiol. (2017) 469:
(8) Kowiański P, Lietzau G, Czuba E, Waśkow M,
Steliga A and Moryś J. BDNF: A Key Factor
with Multipotent Impact on Brain Signaling and
Synaptic Plasticity. Cell. Mol. Neurobiol. (2018)
38: 579-93.
(9) Lima Giacobbo B, Doorduin J, Klein HC, Dierckx
R, Bromberg E and de Vries EFJ. Brain-Derived
Neurotrophic Factor in Brain Disorders: Focus on
Neuroinflammation. Mol. Neurobiol. (2019) 56:
(10) Minichiello L. TrkB signalling pathways in LTP
and learning. Nat. Rev. Neurosci. (2009) 10: 850-
(11) Barker PA. Whither proBDNF? Nat. Neurosci.
(2009) 12: 105-6.
(12) Hanson IM, Seawright A and van Heyningen V.
The human BDNF gene maps between FSHB and
HVBS1 at the boundary of 11p13-p14. Genomics
(1992) 13: 1331-3.
(13) Autry AE and Monteggia LM. Brain-derived
neurotrophic factor and neuropsychiatric disorders.
Pharmacol. Rev. (2012) 64: 238-58.
(14) Ryan KM, Dunne R and McLoughlin DM. BDNF
plasma levels and genotype in depression and
the response to electroconvulsive therapy. Brain
Stimul. (2018) 11: 1123-31.
(15) Casarotto PC, Girych M, Fred SM, Kovaleva V,
Moliner R, Enkavi G, Biojone C, Cannarozzo C,
Sahu MP, Kaurinkoski K, Brunello CA, Steinzeig
A, Winkel F, Patil S, Vestring S, Serchov T,
Diniz C, Laukkanen L, Cardon I, Antila H, Rog
T, Piepponen TP, Bramham CR, Normann C,
Lauri SE, Saarma M, Vattulainen I and Castrén
E. Antidepressant drugs act by directly binding to
TRKB neurotrophin receptors. Cell (2021) 184:
(16) Björkholm C and Monteggia LM. BDNF -
a key transducer of antidepressant effects.
Neuropharmacology (2016) 102: 72-9.
(17) Yang WS, Shi ZG, Dong XZ, Liu P, Chen ML
and Hu Y. Involvement of 5-HT-BDNF signaling
axis in mediating synergistic antidepressantlike effects after combined administration of two
oligosaccharide esters. Food Sci. Nutr. (2021) 9:
(18) Munkholm K, Vinberg M and Kessing LV.
Peripheral blood brain-derived neurotrophic factor
in bipolar disorder: a comprehensive systematic
review and meta-analysis. Mol. Psychiatry (2016)
21: 216-28.
(19) Lin PY. State-dependent decrease in levels of brainderived neurotrophic factor in bipolar disorder: a
meta-analytic study. Neurosci. Lett. (2009) 466:
(20) Rowland T, Perry BI, Upthegrove R, Barnes
N, Chatterjee J, Gallacher D and Marwaha
S. Neurotrophins, cytokines, oxidative stress
mediators and mood state in bipolar disorder:
systematic review and meta-analyses. Br. J.
Psychiatry (2018) 213: 514-25.
(21) Petersen NA, Nielsen M, Coello K, Stanislaus S,
Melbye S, Kjærstad HL, Sletved KSO, McIntyre
RS, Frikke-Smith R, Vinberg M and Kessing
LV. Brain-derived neurotrophic factor levels in
newly diagnosed patients with bipolar disorder,
their unaffected first-degree relatives and healthy
controls. BJPsych Open. (2021) 7: 55.
(22) Mohammadi A, Rashidi E and Amooeian VG.
Brain, blood, cerebrospinal fluid, and serum
biomarkers in schizophrenia. Psychiatry Res.
(2018) 265: 25-38.
(23) Libman-Sokołowska M, Drozdowicz E and
Nasierowski T. BDNF as a biomarker in the course
and treatment of schizophrenia. Psychiatr Pol.
(2015) 49: 1149-58.
(24) Xu H, Wang J, Zhou Y, Chen D, Xiu M, Wang L
and Zhang X. BDNF affects the mediating effect
of negative symptoms on the relationship between
age of onset and cognition in patients with chronic
schizophrenia. Psychoneuroendocrinology (2021)
125: 105121.
(25) Li S, Chen D, Xiu M, Li J and Zhang XY. Diabetes
mellitus, cognitive deficits and serum BDNF levels
in chronic patients with schizophrenia: A casecontrol study. J. Psychiatr. Res. (2021) 134: 39-47.
(26) Soria Lopez JA, González HM and Léger GC.
Alzheimer’s disease. Handb. Clin. Neurol. (2019)
167: 231-55.
(27) Jiao SS, Shen LL, Zhu C, Bu XL, Liu YH, Liu CH,
Yao XQ, Zhang LL, Zhou HD, Walker DG, Tan
J, Götz J, Zhou XF and Wang YJ. Brain-derived
neurotrophic factor protects against tau-related
neurodegeneration of Alzheimer’s disease. Transl. 
BDNF based Nanosystem Delivery
Psychiatry (2016) 6: 907.
(28) Du Y, Wu HT, Qin XY, Cao C, Liu Y, Cao ZZ
and Cheng Y. Postmortem Brain, Cerebrospinal
Fluid, and Blood Neurotrophic Factor Levels in
Alzheimer’s Disease: A Systematic Review and
Meta-Analysis. J. Mol. Neurosci. (2018) 65: 289-
(29) Amidfar M, de Oliveira J, Kucharska E, Budni
J and Kim YK. The role of CREB and BDNF
in neurobiology and treatment of Alzheimer’s
disease. Life Sci. (2020) 257: 118020.
(30) Feng CW, Chen NF, Chan TF and Chen WF.
Therapeutic role of protein tyrosine phosphatase 1B
in parkinson’s disease via antineuroinflammation
and neuroprotection in-vitro and in-vivo.
Parkinsons Dis. (2020) 2020: 8814236.
(31) Palasz E, Wysocka A, Gasiorowska A, Chalimoniuk
M, Niewiadomski W and Niewiadomska G. BDNF
as a Promising Therapeutic Agent in Parkinson’s
Disease. Int. J. Mol. Sci. (2020) 21: 1170.
(32) Ramezani M, Ruskey JA, Martens K, Kibreab M,
Javer Z, Kathol I, Hammer T, Cheetham J, Leveille
E, Martino D, Sarna JR, Gan-Or Z, Pfeffer G, Ismail
Z and Monchi O. Association Between BDNF
Val66Met Polymorphism and Mild Behavioral
Impairment in Patients With Parkinson’s Disease.
Front. Neurol. (2020) 11: 587992.
(33) Iughetti L, Lucaccioni L, Fugetto F, Predieri
B, Berardi A and Ferrari F. Brain-derived
neurotrophic factor and epilepsy: a systematic
review. Neuropeptides (2018) 72: 23-9.
(34) Fernández-García S, Sancho-Balsells A,
Longueville S, Hervé D, Gruart A, Delgado-García
JM, Alberch J and Giralt A. Astrocytic BDNF
and TrkB regulate severity and neuronal activity
in mouse models of temporal lobe epilepsy. Cell
Death Dis. (2020) 11: 411.
(35) Lin TW, Harward SC, Huang YZ and McNamara
JO. Targeting BDNF/TrkB pathways for preventing
or suppressing epilepsy. Neuropharmacology
(2020) 167: 107734.
(36) French MA, Morton SM, Pohlig RT and Reisman
DS. The relationship between BDNF Val66Met
polymorphism and functional mobility in chronic
stroke survivors. Top Stroke Rehabil. (2018) 25:
(37) He Y, Chen S, Tsoi B, Qi S, Gu B, Wang Z, Peng
C and Shen J. Alpinia oxyphylla Miq. and Its
Active Compound P-Coumaric Acid Promote
Brain-Derived Neurotrophic Factor Signaling
for Inducing Hippocampal Neurogenesis and
Improving Post-cerebral Ischemic Spatial
Cognitive Functions. Front. Cell. Dev. Biol. (2020)
8: 577790.
(38) Hasegawa Y, Takemoto Y, Hayashi K, Kameno
K and Kim-Mitsuyama S. The endogenous and
exogenous brain-derived neurotrophic factor plays
pivotal roles in the pathogenesis of stroke onset in
high salt-loaded hypertensive rats. Exp. Gerontol.
(2021) 147: 111286.
(39) Jin H, Ji JJ, Zhu Y, Wang XD, Li YP, Shi QY and
Chen YF. Brain-Derived Neurotrophic Factor, a
New Predictor of Coronary Artery Calcification.
Clin. Appl. Thromb. Hemost. (2021) 27:
(40) Dekeyster E, Geeraerts E, Buyens T, Van den Haute
C, Baekelandt V, De Groef L, Salinas-Navarro M
and Moons L. Tackling Glaucoma from within
the Brain: An Unfortunate Interplay of BDNF and
TrkB. PLoS One. (2015) 10: 142067.
(41) Willoughby CL, Fleuriet J, Walton MM, Mustari
MJ and McLoon LK. Adaptation of slow myofibers:
the effect of sustained BDNF treatment of
extraocular muscles in infant nonhuman primates.
Invest. Ophthalmol. Vis. Sci. (2015) 56: 3467-83.
(42) Konturek TJ, Martinez C, Niesler B, van der Voort
I, Mönnikes H, Stengel A and Goebel-Stengel M.
The Role of Brain-Derived Neurotrophic Factor
in Irritable Bowel Syndrome. Front. Psychiatry
(2020) 11: 531385.
(43) Valvassori SS, Dal-Pont GC, Varela RB, Resende
WR, Gava FF, Mina FG, Budni J and Quevedo
J. Ouabain induces memory impairment and alter
the BDNF signaling pathway in an animal model
of bipolar disorder: Cognitive and neurochemical
alterations in BD model. J. Affect. Disord. (2021)
282: 1195-202.
(44) Béjot Y, Mossiat C, Giroud M, Prigent-Tessier A
and Marie C. Circulating and brain BDNF levels in
stroke rats. Relevance to clinical studies. PLoS One
(2011) 6: 29405.
(45) Furtado D, Björnmalm M, Ayton S, Bush AI,
Kempe K and Caruso F. Overcoming the BloodBrain Barrier: The Role of Nanomaterials in
Treating Neurological Diseases. Adv. Mater.
(2018) 30: 1801362.
(46) Caldas BS, Nunes CS, Panice MR, Scariot DB,
Nakamura CV and Muniz EC. Manufacturing
micro/nano chitosan/chondroitin sulfate curcuminloaded hydrogel in ionic liquid: A new biomaterial
effective against cancer cells. Int. J. Biol.
Macromol. (2021) 180: 88-96.
(47) Saydé T, El Hamoui O, Alies B, Gaudin K, Lespes
G and Battu S. Biomaterials for Three-Dimensional
Cell Culture: From Applications in Oncology to
Nanotechnology. Nanomaterials (2021) 11: 481.
(48) Keefe KM, Sheikh IS and Smith GM. Targeting
Neurotrophins to Specific Populations of Neurons: 
Xia M et al. / IJPR (2021), 20 (4): 137-151
NGF, BDNF, and NT-3 and Their Relevance for
Treatment of Spinal Cord Injury. Int. J. Mol. Sci.
(2017) 18: 548.
(49) Shi Z, Xu Y, Mulatibieke R, Zhong Q, Pan
X, Chen Y, Lian Q, Luo X, Shi Z and Zhu Q.
Nano-Silicate-Reinforced and SDF-1α-Loaded
Gelatin-Methacryloyl Hydrogel for Bone Tissue
Engineering. Int. J. Nanomed. (2020) 15: 9337-53.
(50) Shi W, Nie D, Jin G, Chen W, Xia L, Wu X, Su X,
Xu X, Ni L, Zhang X, Zhang X and Chen J. BDNF
blended chitosan scaffolds for human umbilical
cord MSC transplants in traumatic brain injury
therapy. Biomaterials (2012) 33: 3119-26.
(51) Kandalam S, Sindji L, Delcroix GJ, Violet F, Garric
X, André EM, Schiller PC, Venier-Julienne MC,
des Rieux A, Guicheux J and Montero-Menei CN.
Pharmacologically active microcarriers delivering
BDNF within a hydrogel: Novel strategy for human
bone marrow-derived stem cells neural/neuronal
differentiation guidance and therapeutic secretome
enhancement. Acta Biomater. (2017) 49: 167-80.
(52) Kandalam S, De Berdt P, Ucakar B, Vanvarenberg
K, Bouzin C, Gratpain V, Diogenes A, MonteroMenei CN and des Rieux A. Human dental stem
cells of the apical papilla associated to BDNFloaded pharmacologically active microcarriers
(PAMs) enhance locomotor function after spinal
cord injury. Int. J. Pharm. (2020) 587: 119685.
(53) Sultan MT, Choi BY, Ajiteru O, Hong DK, Lee
SM, Kim HJ, Ryu JS, Lee JS, Hong H, Lee YJ, Lee
H, Suh YJ, Lee OJ, Kim SH, Suh SW and Park CH.
Reinforced-hydrogel encapsulated hMSCs towards
brain injury treatment by trans-septal approach.
Biomaterials (2021) 266: 120413.
(54) Kopec BM, Kiptoo P, Zhao L, Rosa-Molinar E
and Siahaan TJ. Noninvasive Brain Delivery and
Efficacy of BDNF to Stimulate Neuroregeneration
and Suppression of Disease Relapse in EAE Mice.
Mol. Pharm. (2020) 17: 404-16.
(55) Khalin I, Alyautdin R, Wong TW, Gnanou
J, Kocherga G and Kreuter J. Brain-derived
neurotrophic factor delivered to the brain using
poly (lactide-co-glycolide) nanoparticles improves
neurological and cognitive outcome in mice with
traumatic brain injury. Drug Deliv. (2016) 23:
(56) Schmidt N, Schulze J, Warwas DP, Ehlert N, Lenarz
T, Warnecke A and Behrens P. Long-term delivery
of brain-derived neurotrophic factor (BDNF) from
nanoporous silica nanoparticles improves the
survival of spiral ganglion neurons in vitro. PLoS
One (2018) 13: 194778.
(57) Song Z, Ye Y, Zhang Z, Shen J, Hu Z, Wang Z
and Zheng J. Noninvasive, targeted gene therapy
for acute spinal cord injury using LIFU-mediated
BDNF-loaded cationic nanobubble destruction.
Biochem. Biophys. Res. Commun. (2018) 496: 911-
(58) Ghosh B, Wang Z, Nong J, Urban MW, Zhang Z,
Trovillion VA, Wright MC, Zhong Y and Lepore
AC. Local BDNF Delivery to the Injured Cervical
Spinal Cord using an Engineered Hydrogel
Enhances Diaphragmatic Respiratory Function. J.
Neurosci. (2018) 38: 5982-95.
(59) Bhattacharyya S, Dinda A, Vishnubhatla S, Anwar
MF and Jain S. A combinatorial approach to
modulate microenvironment toward regeneration
and repair after spinal cord injury in rats. Neurosci.
Lett. (2021) 741: 135500.
(60) Huang F, Chen T, Chang J, Zhang C, Liao F, Wu
L, Wang W and Yin Z. A conductive dual-network
hydrogel composed of oxidized dextran and
hyaluronic-hydrazide as BDNF delivery systems
for potential spinal cord injury repair. Int. J. Biol.
Macromol. (2021) 167: 434-45.
(61) Pan S, Qi Z, Li Q, Ma Y, Fu C, Zheng S, Kong W,
Liu Q and Yang X. Graphene oxide-PLGA hybrid
nanofibres for the local delivery of IGF-1 and
BDNF in spinal cord repair. Artif. Cells Nanomed.
Biotechnol. (2019) 47: 651-64.
(62) Hassannejad Z, Zadegan SA, Vaccaro AR, RahimiMovaghar V and Sabzevari O. Biofunctionalized
peptide-based hydrogel as an injectable scaffold
for BDNF delivery can improve regeneration after
spinal cord injury. Injury (2019) 50: 278-85.
(63) Yang S, Wang C, Zhu J, Lu C, Li H, Chen F, Lu J,
Zhang Z, Yan X, Zhao H, Sun X, Zhao L, Liang
J, Wang Y, Peng J and Wang X. Self-assembling
peptide hydrogels functionalized with LN- and
BDNF- mimicking epitopes synergistically enhance
peripheral nerve regeneration. Theranostics (2020)
10: 8227-49.
(64) Fukushima Y, Uchida S, Imai H, Nakatomi H,
Kataoka K, Saito N and Itaka K. Treatment of
ischemic neuronal death by introducing brainderived neurotrophic factor mRNA using polyplex
nanomicelle. Biomaterials (2021) 270: 120681.
(65) Braschi C, Capsoni S, Narducci R, Poli A,
Sansevero G, Brandi R, Maffei L, Cattaneo A and
Berardi N. Intranasal delivery of BDNF rescues
memory deficits in AD11 mice and reduces brain
microgliosis. Aging Clin. Exp. Res. (2021) 33:
(66) Padmakumar S, Jones G, Pawar G, Khorkova
O, Hsiao J, Kim J, Amiji MM and Bleier BS.
Minimally Invasive Nasal Depot (MIND)
technique for direct BDNF AntagoNAT delivery to
the brain. J. Control. Release (2021) 331: 176-86.
BDNF based Nanosystem Delivery
(67) Cook DJ, Nguyen C, Chun HN, I LL, Chiu AS,
Machnicki M, Zarembinski TI and Carmichael ST.
Hydrogel-delivered brain-derived neurotrophic
factor promotes tissue repair and recovery after
stroke. J. Cereb. Blood Flow Metab. (2017) 37:
(68) Lopes CDF, Gonçalves NP, Gomes CP, Saraiva MJ
and Pêgo AP. BDNF gene delivery mediated by
neuron-targeted nanoparticles is neuroprotective in
peripheral nerve injury. Biomaterials (2017) 121:
(69) Lu J, Yan X, Sun X, Shen X, Yin H, Wang C, Liu Y,
Lu C, Fu H, Yang S, Wang Y, Sun X, Zhao L, Lu S,
Mikos AG, Peng J and Wang X. Synergistic effects
of dual-presenting VEGF- and BDNF-mimetic
peptide epitopes from self-assembling peptide
hydrogels on peripheral nerve regeneration.
Nanoscale (2019) 11: 19943-58.
(70) Loy TL, Vehlow D, Kauschke V, Müller M,
Heiss C and Lips KS. Effects of BDNF and PEC
Nanoparticles on Osteocytes. Molecules (2020) 25:
(71) Jimbo R, Singer J, Tovar N, Marin C, Neiva R,
Bonfante EA, Janal MN, Contamin H, and Coelho
PG. Regeneration of the cementum and periodontal
ligament using local BDNF delivery in class II
furcation defects. J. Biomed. Mater. Res. Appl.
Biomater. (2018) 106: 1611-7.