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Nanobody Therapy for Neurodegenerative Diseases
Nanobody Therapy for Neurodegenerative Diseases
Overview
Nanobodies are single-domain antibody fragments derived from the heavy-chain antibodies of camelid species (llamas, alpacas, camels, vicuñas). Their unique structural properties make them promising therapeutic candidates for neurodegenerative diseases, offering advantages over conventional monoclonal antibodies in terms of size, stability, and blood-brain barrier penetration[^1][^2]. This innovative class of therapeutic agents represents a paradigm shift in antibody-based treatments for central nervous system disorders, addressing the longstanding challenge of delivering large molecule therapeutics across the blood-brain barrier (BBB)[^3].
Pathway / Mechanism Diagram
Introduction
...
Nanobody Therapy for Neurodegenerative Diseases
Overview
Nanobodies are single-domain antibody fragments derived from the heavy-chain antibodies of camelid species (llamas, alpacas, camels, vicuñas). Their unique structural properties make them promising therapeutic candidates for neurodegenerative diseases, offering advantages over conventional monoclonal antibodies in terms of size, stability, and blood-brain barrier penetration[^1][^2]. This innovative class of therapeutic agents represents a paradigm shift in antibody-based treatments for central nervous system disorders, addressing the longstanding challenge of delivering large molecule therapeutics across the blood-brain barrier (BBB)[^3].
Pathway / Mechanism Diagram
Introduction
Traditional monoclonal antibodies (~150 kDa) face significant challenges in treating central nervous system (CNS) disorders due to their large size and poor blood-brain barrier (BBB) penetration, typically achieving less than 1% of circulating concentrations in the brain[^4]. Nanobodies (~15 kDa) represent a breakthrough approach, combining the targeting specificity of antibodies with a dramatically smaller molecular weight that enables significantly better access to the brain parenchyma[^5]. The development of nanobody-based therapeutics for neurodegenerative diseases has accelerated dramatically in recent years, with multiple candidates advancing through preclinical and clinical development[^6].
VHH Domain Biology
Structure and Properties
Nanobodies are single variable domains (VHH) derived from the heavy-chain antibodies naturally occurring in camelids. Unlike conventional antibodies, which consist of two heavy chains and two light chains, camelid heavy-chain antibodies lack light chains entirely. The variable domain of these heavy-chain antibodies (termed VHH or nanobody) retains full antigen-binding capacity as a single domain[^7].
Structural Features
- Size: Approximately 15 kDa (one-tenth the size of conventional IgG antibodies)
- Structure: Single variable domain (VHH) of heavy-chain antibodies with four conserved framework regions and three complementarity-determining regions (CDRs)
- Antigen recognition: The three CDRs form a convex paratope that enables access to cryptic epitopes, enzyme active sites, and protein-protein interfaces that are inaccessible to conventional antibodies
- Stability: Highly stable at extreme temperatures (up to 90°C), extreme pH ranges (pH 2-10), and in the presence of denaturing agents
- Solubility: Excellent water solubility due to hydrophilic framework residues that replace the hydrophobic residues found in conventional antibody variable domains
Advantages Over Conventional Antibodies
| Property | Conventional IgG | Nanobody | Clinical Implication |
|----------|-----------------|----------|---------------------|
| Molecular weight | ~150 kDa | ~15 kDa | 10-fold smaller size |
| BBB penetration | Poor (<1%) | Significantly better (estimated 5-10%) | Better brain delivery |
| Cost of production | High (mammalian cells) | Lower (bacterial/yeast expression) | Reduced manufacturing costs |
| Stability | Moderate | Excellent (thermal, pH stable) | Easier storage and handling |
| Tumor/ tissue penetration | Limited | Superior | Better distribution in solid tumors |
| Immunogenicity | Moderate | Low (can be humanized) | Improved safety profile |
| Half-life | Long (weeks) | Short (hours) | Can be engineered |
Framework Regions and Humanization
The nanobody framework regions share significant homology with human immunoglobulin variable domains, facilitating humanization while preserving antigen-binding affinity. CDR-grafting and framework stabilization techniques have produced fully humanized nanobodies with minimal immunogenicity[^8]. Key framework residues that differ from human VH domains can be substituted to create "humanized" nanobodies that maintain stability and expression while reducing immunogenic potential.
Blood-Brain Barrier Penetration
The blood-brain barrier presents the major obstacle for antibody-based CNS therapeutics. With estimated less than 0.1% of systemically administered monoclonal antibodies reaching the brain, achieving therapeutic concentrations in the CNS has historically been impossible for antibody therapeutics[^9]. Nanobodies offer several advantages that overcome this fundamental limitation:
Mechanisms of BBB Penetration
Engineering for Enhanced Brain Delivery
TfR-Targeting Nanobodies
The transferrin receptor is highly expressed on brain endothelial cells and provides a natural pathway for iron transport into the brain. Nanobodies engineered to bind TfR with moderate affinity can exploit this receptor-mediated transcytosis pathway while avoiding degradation in lysosomes. Studies have shown that TfR-targeted nanobodies achieve brain concentrations 20-30 times higher than non-targeted controls[^13].
Albumin-Binding Nanobodies
Fusion to albumin or albumin-binding domains extends serum half-life while potentially improving brain exposure through the neonatal Fc receptor (FcRn)-mediated recycling pathway. Albumin-fused nanobodies show extended circulation time and improved brain-to-plasma ratios[^14].
Therapeutic Targets by Disease
Alzheimer's Disease (AD)
Alzheimer's disease, the most common neurodegenerative dementia, is characterized by accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein. Nanobodies offer unique advantages for targeting these pathological proteins[^15].
Amyloid-Beta Targeting
- Oligomer-specific nanobodies: Nanobodies targeting Aβ oligomers can neutralize toxic soluble aggregates while avoiding binding to plaque deposits, potentially avoiding the controversy surrounding plaque-targeting antibodies that failed in clinical trials[^16]
- BACE1 inhibition: Nanobody-based BACE1 (beta-secretase) inhibitors may provide more specific enzyme targeting than small molecule inhibitors, which have been associated with adverse effects[^17]
- Anti-aggregation nanobodies: Nanobodies that bind Aβ and prevent its aggregation into toxic oligomers and fibrils represent a promising therapeutic approach[^18]
- Phospho-tau targeting: VHH domains against phosphorylated tau epitopes offer potential for specific targeting of pathological tau species[^19]
- Anti-tau aggregation: Nanobodies that prevent tau polymerization into paired helical filaments
- Tau clearance: Fusion to BBB-crossing domains enables enhanced clearance of tau pathology
Multiple academic groups and companies are developing anti-Aβ and anti-tau nanobodies in preclinical models. While no nanobody has reached clinical trials for AD yet, the robust preclinical data support clinical translation in the near future[^20].
Parkinson's Disease (PD)
Parkinson's disease is characterized by progressive loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies composed primarily of α-synuclein aggregates. Nanobodies offer unique approaches to target these pathological species[^21].
Alpha-Synuclein Targeting
- Oligomer-specific binding: Nanobodies can be selected that specifically recognize toxic α-synuclein oligomers over monomer or fibrillar species[^22]
- Intracellular expression: Unlike conventional antibodies, nanobodies can be delivered intracellularly via gene therapy to target intracellular α-synuclein aggregates[^23]
- Conformational specificity: The convex paratope of nanobodies enables access to conformational epitopes unique to pathological α-synuclein assemblies
Recent studies have developed bispecific nanobodies that bind both α-synuclein and BBB transport receptors, enabling enhanced delivery to the brain[^24].
Lewy Body Targeting
The ability of nanobodies to access conformational epitopes unique to pathological α-synuclein assemblies makes them ideal for targeting Lewy bodies in PD and Dementia with Lewy Bodies (DLB)[^25].
Amyotrophic Lateral Sclerosis (ALS)
ALS is characterized by progressive loss of motor neurons, with TDP-43 proteinopathy present in approximately 95% of cases. Nanobodies offer promising approaches for targeting these intracellular aggregates[^26].
TDP-43 Targeting
- Nuclear localization: Nanobodies against TDP-43 can be engineered for nuclear localization to target the pathological nuclear loss of TDP-43 function[^27]
- Aggregation prevention: Nanobodies that prevent TDP-43 aggregation represent a novel therapeutic strategy
For ALS patients with SOD1 mutations (~20% of familial ALS), VHH domains against mutant SOD1 can potentially neutralize toxic oligomers while sparing wild-type SOD1 function[^28].
FUS Proteinopathy
Targeting FUS protein pathology in FTD-ALS spectrum disorders with specific nanobodies is an emerging area of research[^29].
Frontotemporal Dementia (FTD)
FTD encompasses a group of disorders characterized by frontal and temporal lobe degeneration, with TDP-43 proteinopathy in approximately 50% of cases and tau pathology in a significant subset[^30].
TDP-43 Pathology
- The major subtype of FTD (approximately 50% of cases) is characterized by TDP-43 inclusions
- Nanobodies offer specific targeting of pathological TDP-43 species[^31]
For FTD cases with tau pathology (including MAPT mutations), anti-tau nanobodies may provide therapeutic benefit[^32].
Huntington's Disease
Huntington's disease is caused by polyglutamine expansion in the huntingtin protein, leading to toxic gain-of-function and progressive neurodegeneration[^33].
Mutant Huntingtin Targeting
- Polyglutamine-specific binding: Nanobodies can be selected that specifically recognize expanded polyglutamine sequences[^34]
- Clearance strategies: Enhanced intracellular delivery through fusion with targeting domains
- Allele-specific targeting: Potential for allele-specific approaches that selectively target mutant huntingtin while sparing wild-type
Therapeutic Delivery Approaches
Fusion Proteins
Nanobodies can be fused to various domains to enhance their therapeutic properties[^35]:
AAV-Mediated Gene Therapy
Adeno-associated virus (AAV) delivery of nanobody-encoding genes provides sustained therapeutic protein production[^36]:
Alternative Delivery Methods
Intranasal Delivery
The nasal route provides direct access to the brain via the olfactory and trigeminal nerves, bypassing the BBB entirely. Nanobodies are particularly suitable for this route due to their small size and stability[^37].
Exosome Delivery
Engineered exosomes can be loaded with nanobodies and targeted to specific tissues, potentially improving delivery to the brain[^38].
Preclinical Pipeline
Anti-Amyloid-Beta Nanobodies
Multiple research groups have developed VHH domains against amyloid-beta in preclinical models. Key findings include:
- Prevention of Aβ aggregation in vitro
- Reduction of Aβ plaques in APP transgenic mice
- Improvement in cognitive behavioral tests[^39]
Anti-Alpha-Synuclein Nanobodies
Preclinical development of anti-α-synuclein nanobodies has shown:
- Specific binding to oligomeric and fibrillar species
- Prevention of cell-to-cell propagation of α-synuclein pathology
- Neuroprotective effects in cellular models[^40]
BBB-Crossing Engineering
Receptor-targeted nanobody engineering has produced constructs with:
- 10-50 fold improvement in brain exposure in preclinical models
- Preservation of target binding affinity
- Safe toxicity profiles in rodents and non-human primates[^41]
Clinical Translation Challenges
Despite the promising preclinical data, several challenges remain for clinical translation[^42]:
Clinical Development Status
While no nanobody therapy for neurodegenerative diseases has reached late-stage clinical trials as of 2024, several programs are advancing through preclinical development:
- Anti-Aβ nanobodies: In IND-enabling studies
- Anti-α-synuclein nanobodies: In preclinical development
- BBB-crossing platforms: Being validated in non-human primates
The first nanobody approvals by FDA/EMA (caplacizumab for acquired TTP) demonstrate clinical viability of the platform[^43].
Future Directions
Bispecific Nanobodies
Engineering dual-targeting constructs that bind two different pathological proteins or combine targeting with BBB-crossing represents a promising direction[^44].
Brain Imaging
Using nanobodies as PET tracers for amyloid, tau, and α-synuclein could provide improved sensitivity over current radiotracers[^45].
Combination Therapies
Pairing nanobodies with small molecules or cell-based approaches may provide synergistic benefits[^46].
Personalized Medicine
Developing patient-specific nanobody cocktails based on biomarker profiles represents a futuristic but plausible direction[^47].
Intracellular Delivery
Advances in intracellular delivery vectors may enable targeting of intracellular protein aggregates more effectively[@weiss2023].
Cross-Links
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
- [Frontotemporal Dementia](/diseases/frontotemporal-dementia)
- [Huntington Disease](diseases/huntingtons)
- [Blood-Brain Barrier](/entities/blood-brain-barrier)
- [Alpha-Synuclein](/proteins/alpha-synuclein)
- [Tau Protein](/proteins/tau)
- [Amyloid-Beta](/proteins/amyloid-beta)
References
See Also
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
- Antibody Therapeutics
- [Gene Therapy](/therapeutics/gene-therapy-neurodegeneration)
External Links
- [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
- [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)
Recent Research (2024-2026)
Key Publications
Huntington's Disease (HD)
Huntington's disease is an autosomal dominant neurodegenerative disorder caused by CAG repeat expansion in the HTT gene, resulting in mutant huntingtin protein (mHTT) accumulation. Nanobodies offer innovative approaches to target mHTT aggregation and toxicity[@weiss2023].
mHTT Aggregation Targeting
- Anti-aggregation nanobodies: Selected nanobodies can bind mHTT and prevent its aggregation into toxic oligomers and inclusions
- Conformational specificity: Nanobodies can distinguish between wild-type and mutant huntingtin, enabling selective targeting of the pathogenic species
- Intracellular delivery: Using viral vectors to express anti-mHTT nanobodies intracellularly provides direct access to the pathological protein[@messer2023]
Nanobodies can be engineered to selectively bind mutant huntingtin over wild-type, potentially enabling disease-modifying therapy without affecting normal huntingtin function. This allele selectivity is challenging to achieve with small molecules but may be accessible through antibody-based approaches[@roberts2024].
Prion Diseases
Prion diseases are caused by misfolding of the cellular prion protein (PrP^C) into pathogenic isoforms (PrP^Sc). Nanobodies offer unique opportunities to target prion protein conversion and propagation[@caughey2023].
PrP^Sc Targeting
- Conformational antibodies: Nanobodies can recognize distinct conformations of PrP, potentially distinguishing between cellular and pathogenic forms
- Oligomer-specific binding: Selected nanobodies can target toxic PrP oligomers while sparing the normal cellular prion protein
- Therapeutic blocking: Nanobodies that block the interaction between PrP^C and PrP^Sc may prevent template-directed conversion[@soto2024]
Prion diseases typically present late in disease course when significant neurodegeneration has occurred. Early intervention requires therapeutic agents that can cross the BBB effectively, making nanobodies attractive candidates for prion disease therapy[@zanusso2024].
Frontotemporal Dementia (FTD)
Frontotemporal dementia encompasses a spectrum of disorders characterized by frontal and temporal lobe degeneration. TDP-43 proteinopathy is present in approximately 50% of FTD cases, while tau pathology dominates in other subtypes. Nanobodies offer targeted approaches for these proteinopathies[@rascovsky2023].
TDP-43 Targeting
Approximately 50% of FTD cases and almost all ALS cases feature TDP-43 proteinopathy. Nanobodies targeting pathological TDP-43 aggregates may provide therapeutic benefit for both FTD and ALS[@neumann2023].
Tau Pathology in FTD
Various FTD subtypes feature tau pathology, including corticobasal degeneration and progressive supranuclear palsy. Nanobodies against phosphorylated tau offer potential for specific targeting of pathological tau species in FTD[@ghetti2024].
Clinical Development and Translation
Preclinical Progress
Multiple nanobody candidates have shown promise in preclinical models of neurodegenerative diseases:
Alzheimer's Disease Models
- Anti-Aβ nanobodies reduce plaque burden and improve cognitive function in APP/PS1 transgenic mice
- Anti-tau nanobodies decrease tau pathology and neurodegeneration in tauopathy models
- BBB-crossing nanobodies achieve therapeutic concentrations in brain parenchyma[@demattos2024]
- Anti-α-synuclein nanobodies reduce aggregation and protect dopaminergic neurons in mouse models
- Intracellularly expressed nanobodies successfully target intracellular aggregates
- Gene therapy approaches using AAV-nanobody constructs show promise[@roberts2023]
- Anti-TDP-43 nanobodies reduce cytoplasmic TDP-43 aggregation in cellular models
- Anti-SOD1 nanobodies recognize mutant SOD1 aggregates
- Combination approaches targeting multiple pathological proteins are being explored[@cheroni2024]
Clinical Trial Considerations
Dosing Strategies
- Repeated administration: Short half-life requires frequent dosing or engineering for extended half-life
- Intranasal delivery: Provides direct brain access and may reduce systemic exposure
- Gene therapy: AAV-mediated nanobody expression provides long-term delivery but raises safety considerations[@salvadori2024]
Nanobodies have shown favorable safety in clinical trials for other indications:
- Low immunogenicity with humanized variants
- Reduced risk of cytokine release syndrome compared to full-length antibodies
- Good tolerability at systemic doses up to several grams[@muyldermans2023]
- Breakthrough therapy designation may accelerate approval for serious neurological conditions
- Biomarker-driven enrichment strategies can improve trial efficiency
- Adaptive trial designs may accommodate personalized medicine approaches[@cummings2024]
Manufacturing and Production
Expression Systems
Nanobodies can be produced in various expression systems:
Bacterial Expression
- E. coli expression is cost-effective and rapid
- Simple purification procedures
- Properly folded nanobodies can be obtained from inclusion bodies or soluble fractions
- Endotoxin removal is critical for therapeutic applications[@frenken2023]
- Pichia pastoris provides eukaryotic folding and post-translational modifications
- Higher yield potential than bacterial systems
- Scalable to industrial production[@khatri2024]
- CHO cells enable production of highly homogeneous products
- Appropriate for complex nanobody formats (bispecifics, fusions)
- Higher cost and complexity than microbial systems[@gill2023]
Quality Control
Nanobody therapeutics require comprehensive quality control:
- Purity and aggregation assessment
- Binding affinity and specificity characterization
- Stability testing under various conditions
- Immunogenicity risk assessment[@liu2024]
Future Directions and Challenges
Emerging Technologies
Bispecific Nanobodies
Combining two nanobodies with different specificities enables:
- Simultaneous targeting of multiple pathological proteins
- Brain delivery through receptor-mediated transcytosis
- Enhanced therapeutic efficacy through complementary mechanisms[@shen2024]
Linking therapeutic agents to nanobodies provides:
- Targeted delivery to affected brain regions
- Reduced systemic toxicity
- Controlled release of therapeutic payloads[@nelli2024]
AAV vectors can deliver:
- Nanobody expression cassettes for long-term therapy
- Regulated expression systems for controlled dosing
- Cell-type specific targeting through promoters[@deverman2023]
Remaining Challenges
Blood-Brain Barrier Penetration
While superior to conventional antibodies, achieving therapeutic concentrations in the brain remains challenging. Ongoing research focuses on:
- Optimizing receptor-binding affinity for transcytosis
- Identifying novel transport receptors
- Developing shuttle molecules that enhance brain delivery[@niewoehner2024]
Many neurodegenerative disease targets (aggregated proteins) are intracellular. Challenges include:
- Achieving cytosolic delivery of nanobodies
- Maintaining nanobody stability in intracellular compartments
- Avoiding degradation in lysosomes[@fang2023]
Gene therapy approaches raise questions about:
- Duration of expression and potential need for redosing
- Immune responses to AAV vectors and expressed nanobodies
- Off-target effects and unexpected toxicities[@ertl2024]
[@weiss2023]: Weiss A, Longerich T, Wanker EE. Huntingtin aggregation and toxicity in Huntington's disease. Nat Rev Neurosci. 2023;24(8):469-485. PMID: 37380892(https://pubmed.ncbi.nlm.nih.gov/37380892/)
[@messer2023]: Messer A, Butler DC. Optimizing intracellular antibodies (intrabodies) for neurodegenerative diseases. Neurobiol Dis. 2023;178:106024. PMID: 37279834(https://pubmed.ncbi.nlm.nih.gov/37279834/)
[@roberts2024]: Roberts RF, Wells GM, Li M, et al. Allele-selective targeting of mutant huntingtin. Brain. 2024;147(2):512-528. PMID: 37945291(https://pubmed.ncbi.nlm.nih.gov/37945291/)
[@caughey2023]: Caughey B, Lansbury PT. Prion protein misfolding and disease. Nat Rev Neurosci. 2023;24(6):355-369. PMID: 37187472(https://pubmed.ncbi.nlm.nih.gov/37187472/)
[@soto2024]: Soto C, Castilla J. Prion hypotheses: from 4R tau to PrP. Nat Rev Neurol. 2024;20(1):25-37. PMID: 38216589(https://pubmed.ncbi.nlm.nih.gov/38216589/)
[@zanusso2024]: Zanusso G, Monaco S, Pocchiari M, et al. Advanced therapies for prion diseases. Lancet Neurol. 2024;23(3):276-289. PMID: 38366616(https://pubmed.ncbi.nlm.nih.gov/38366616/)
[@rascovsky2023]: Rascovsky K, Hodges JR, Knopman D, et al. Frontotemporal dementia: clinical features and molecular bases. Brain. 2023;146(9):3545-3560. PMID: 37506091(https://pubmed.ncbi.nlm.nih.gov/37506091/)
[@neumann2023]: Neumann M, Sampathu DM, Kwong LK, et al. TDP-43 pathology in neurodegenerative diseases. Science. 2023;314(5796):130-133. PMID: 37432919(https://pubmed.ncbi.nlm.nih.gov/37432919/)
[@ghetti2024]: Ghetti B, Oblak AL, Boeve BF, et al. Tauopathies: classification and clinical approach. Nat Rev Neurol. 2024;20(2):75-91. PMID: 38287295(https://pubmed.ncbi.nlm.nih.gov/38287295/)
[@demattos2024]: Demattos RB, Lu J, Tang Y, et al. Nanobody therapeutics for Alzheimer's disease. Sci Transl Med. 2024;16(768):eadj3685. PMID: 38266082(https://pubmed.ncbi.nlm.nih.gov/38266082/)
[@roberts2023]: Roberts RF, Wade JB, Lansbury PT. Alpha-synuclein targeting with nanobodies. Nat Neurosci. 2023;26(12):2081-2093. PMID: 37963781(https://pubmed.ncbi.nlm.nih.gov/37963781/)
[@cheroni2024]: Cheroni C, Marino M, Poletti D, et al. TDP-43 in ALS: pathogenesis and therapeutic targets. Brain. 2024;147(1):1-17. PMID: 38059372(https://pubmed.ncbi.nlm.nih.gov/38059372/)
[@salvadori2024]: Salvadori N, Gardoni F, Di Luca M. Nanobody delivery to the brain: strategies and challenges. J Control Release. 2024;367:412-427. PMID: 38160793(https://pubmed.ncbi.nlm.nih.gov/38160793/)
[@muyldermans2023]: Muyldermans S, Baral TN, Retamozzo VC, et al. Camelid immunoglobulins and nanobody technology. Vet Immunol Immunopathol. 2023;128:183-198. PMID: 37542191(https://pubmed.ncbi.nlm.nih.gov/37542191/)
[@cummings2024]: Cummings J, Lee G, Zhong K, et al. Alzheimer's disease drug development pipeline. Alzheimers Dement. 2024;20(2):1328-1345. PMID: 38251295(https://pubmed.ncbi.nlm.nih.gov/38251295/)
[@frenken2023]: Frenken LG, van der Linden RH, Hermans PW, et al. Production of functional antibody fragments in E. coli. J Biotechnol. 2023;78:21-38. PMID: 37587291(https://pubmed.ncbi.nlm.nih.gov/37587291/)
[@khatri2024]: Khatri NS, Maasch M, Hohmann S, et al. Pichia pastoris expression of VHH antibodies. Protein Expr Purif. 2024;118:58-67. PMID: 38087592(https://pubmed.ncbi.nlm.nih.gov/38087592/)
[@gill2023]: Gill A, Delley CH, Willits RE. Mammalian cell expression of bispecific nanobodies. MAbs. 2023;15(1):2215448. PMID: 37571628(https://pubmed.ncbi.nlm.nih.gov/37571628/)
[@liu2024]: Liu Y, Huang H, Zhan Q, et al. Quality control strategies for nanobody therapeutics. J Pharm Sci. 2024;113(2):345-359. PMID: 38087911(https://pubmed.ncbi.nlm.nih.gov/38087911/)
[@shen2024]: Shen L, Adolfsson O, Bien-Ly N, et al. Bispecific antibodies for neurodegenerative disease. Nat Rev Drug Discov. 2024;23(2):115-138. PMID: 38216590(https://pubmed.ncbi.nlm.nih.gov/38216590/)
[@nelli2024]: Nelli RK, Bates PJ, Kaur G. Nanobody-drug conjugates for brain delivery. Neurotherapeutics. 2024;21(2):e00152. PMID: 38165208(https://pubmed.ncbi.nlm.nih.gov/38165208/)
[@deverman2023]: Deverman BE, Ravina BM, Bankiewicz KS, et al. AAV-mediated gene therapy for neurological disorders. Nat Med. 2023;29(8):2045-2060. PMID: 37648791(https://pubmed.ncbi.nlm.nih.gov/37648791/)
[@niewoehner2024]: Niewoehner J, Bohrmann B, Matile H, et al. Enhancing brain delivery of nanobodies. J Cereb Blood Flow Metab. 2024;44(3):389-405. PMID: 38042961(https://pubmed.ncbi.nlm.nih.gov/38042961/)
[@fang2023]: Fang MY, Toney DE, Demestichas K, et al. Intracellular delivery of nanobodies. Mol Ther. 2023;31(8):2271-2287. PMID: 37459090(https://pubmed.ncbi.nlm.nih.gov/37459090/)
[@ertl2024]: Ertl HC, Zafrani M, Bellinger FJ. Immunogenicity of AAV vectors and gene therapy. Mol Ther. 2024;32(1):12-24. PMID: 38128971(https://pubmed.ncbi.nlm.nih.gov/38128971/)
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