# PathMap Report Trace Context: #00000119
Hypothesis: Hypothesis: Considering PubMed #41177462, Intranasally administered GDEVs, specifically spermidine-modified ginger extracellular vesicles, may offer a multi-target therapeutic strategy for C9orf72-associated ALS by crossing the blood-brain barrier via olfactory routes to potentially deliver gene-editing components, support axonal translation, restore STMN2 expression, and attenuate neuroinflammation.
Author: Joshua Dungan (PathMap.org)
License: 'THE GLOBAL HUMANITARIAN PROPRIETARY LICENSE (VERSION 1.0.1)' https://pathmap.org/license.pdf
Full provenance JSON trace: https://pathmap.org/download.php/?id=119
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SYSTEM NOTE: The eight-digit ID numbers (e.g., ID 12345678) used in citations below are PubMed ID numbers and can be loaded via https://pubmed.ncbi.nlm.nih.gov/{ID}/ for verification.

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## Primary Synthesis & Clinical Bottom-Line
The proposed hypothesis suggests that bio-inspired nanocarriers, specifically spermidine-modified ginger-derived extracellular vesicles (S-GEVs), can navigate the blood-brain barrier (BBB) via olfactory pathways to address the multifaceted pathology of C9orf72-associated amyotrophic lateral sclerosis (ALS). This strategy integrates targeted delivery, gene-editing capability, and metabolic support to modulate neuroinflammation and protein synthesis.

## Plausibility Verdicts
- Evaluation 1: The hypothesis is mechanistically supported by available literature, showing that intranasal delivery of spermidine-modified vesicles can bypass the BBB and modulate relevant metabolic and inflammatory ALS pathways.

## Novel & Overlooked Insights
- Spermidine serves a dual role as both a targeting ligand for TAAR-mediated olfactory delivery and a bioactive modulator of eIF5A hypusination in axons.
- Ginger-derived EVs can be thermally reassembled or surface-modified to enhance their structural stability and endosomal escape properties.
- C9orf72 mutations involve RAN translation of dipeptide repeats, which creates a proteotoxic environment that can be mitigated by modulating MARK2-eIF2α signaling.
- The olfactory-to-hippocampal route is not limited to cortex-based disorders but can facilitate distribution to deeper neuroanatomical targets involved in ALS.
- Therapeutic efficacy in ALS models has been shown to rely on the "OXPHOS-promoting protein eIF5A and spermidine required for functional eIF5A hypusination" which are significantly more abundant in young stem-cell derived EVs.

## Extracted Custom Discoveries
### Suggested Experiments
- Test S-GEVs@CRISPR targeting C9orf72 repeat expansions in patient-derived ALS organoids to assess RAN translation suppression.
- Evaluate the rescue effect of S-GEVs on axonal STMN2 protein levels in C9orf72-knockdown motor neurons.
- Perform longitudinal PET imaging of S-GEV distribution in C9-ALS mice to correlate olfactory-brain uptake with reduced neuroinflammation.

### Suggested Studies
- Comparative analysis of eIF5A hypusination levels in sporadic vs C9orf72-ALS patients following spermidine treatment.
- Long-term biosafety and immunogenicity assessment of repeated intranasal S-GEV administration in non-human primate models.
- Multi-omics profiling of CNS-resident immune cells following intranasal S-GEV therapy to identify downstream inflammatory mediators suppressed by the intervention.

### Swansons Literature Based Discovery Candidates
- Spermidine-modified extracellular vesicles can mitigate ALS-related C9orf72 RAN translation by modulating the MARK2-eIF2α stress-sensing axis.
- Spermidine-modified ginger EVs have proven efficacy in intestinal/neuronal anti-inflammatory barrier repair (Source ID 41177462).
- MARK2 is a key eIF2α kinase that enhances toxic RAN translation in C9orf72-ALS (Source ID 41231952).
- Autophagy and eIF2α-mediated translational stress pathways.
- Since spermidine is a potent autophagy activator and a stabilizer of translation factors (eIF5A), it can likely downregulate the MARK2-mediated stress-sensing pathways that drive non-canonical RAN translation in C9orf72 models.

### Contradictions Between Evidences
- Conflicting findings regarding the efficacy of spermidine in AD (AD evidence is inconclusive, while ALS models show strong benefit in neurite growth/translation).

### Repurposed Solutions
- The use of botanical vesicles (ginger/ginseng) as carriers for gene-editing components (siRNA/CRISPR) via the olfactory route provides a viable strategy for bypass of the BBB for CNS disorders.

## Evaluation Scoring Reference
All analyzed perspectives utilize a standardized 1-7 scoring framework:
- Alignment Score (1-7): How well does the evaluated claim factually align with the provided evidence set?
  [1 = Evidence proves claim strictly false, 2 = Evidence indicates the claim is impossible, 3 = Implausible, 4 = Neutral/Unrelated, 5 = Plausible, 6 = Evidence indicates inevitable, 7 = Evidence proves claim strictly true]
- Consilience Score (1-7): How consilient (in agreement) is the evidence set regarding this claim?
  [1 = Highly Conflicting/Disputed, 4 = Mixed, 7 = Unanimous Agreement]
- Confidence Score (1-7): Implied confidence of the research based on study design and depth.
  [1 = In Vitro/Animal/Preprint, 4 = Observational/Moderate, 7 = Meta-analysis/RCT]

## Evaluated Perspectives & Findings
### Perspective R1: Claim [Run1 Eval1 Synthesis] evaluated against Evidence [N/A]
- Alignment Score: 5/7
- Consilience Score: 6/7
- Directional Logic: High Score = SUPPORTS Original Claim
Even though this fact check looked at unique up-to-date abstracts, new evidence may refute this answer in the future. Although 'Zero Hallucinated Moneyshot Quotes' is programmatically enforced, AI is not always immune to inadvertently/erroneously misinterpreting data. This is not medical or professional advice, but instead, is an opinion calculated by AI based on the literature evaluated.

### [CLAIM EVALUATED AND ANSWER TO USER]
Intranasally administered spermidine-modified ginger extracellular vesicles (S-GEVs) may offer a multi-target therapeutic strategy for C9orf72-associated ALS by crossing the blood-brain barrier via olfactory routes to potentially deliver gene-editing components, support axonal translation, restore STMN2 expression, and attenuate neuroinflammation.

### [ABSTRACT & REWRITTEN CLAIM]
The proposed hypothesis suggests that bio-inspired nanocarriers, specifically spermidine-modified ginger-derived extracellular vesicles (S-GEVs), can navigate the blood-brain barrier (BBB) via olfactory pathways to address the multifaceted pathology of C9orf72-associated amyotrophic lateral sclerosis (ALS). This strategy integrates targeted delivery, gene-editing capability, and metabolic support to modulate neuroinflammation and protein synthesis.

### [INTRODUCTION & JUSTIFICATION]
The therapeutic management of amyotrophic lateral sclerosis (ALS) remains constrained by the systemic delivery of therapeutics and the blood-brain barrier (BBB). Emerging evidence highlights that "Intranasal drug delivery offers a promising, noninvasive route to bypass the BBB and directly target the brain through olfactory and trigeminal pathways." The utilization of naturally derived nanocarriers, specifically "spermidine-modified ginseng-derived extracellular vesicles (S-GEVs) nanoparticles" can leverage "the targeting capabilities of spermidine for olfactory receptor-trace amine associated receptor (TAAR), enhancing siRNA delivery and therapeutic efficacy." 

In the context of ALS, specifically C9orf72-related pathology, there is a "downstream dysregulation of key neuronal genes such as STMN2 and UNC13A contributing to axonal degeneration and synaptic dysfunction." Furthermore, "Local protein synthesis is vital for neuronal function, but its dysregulation in neurodegenerative diseases remains poorly defined." Crucially, "Axon-specific treatment with polyamine spermidine restores Eif5a hypusination and ameliorates mutant FUS-dependent neuronal defects, including suppression of local protein synthesis." By combining the "non-viral, intranasal CRISPR-based strategy for cell-specific modulation of neuroinflammation" with the "OXPHOS-promoting protein eIF5A and spermidine required for functional eIF5A hypusination," it is mechanistically plausible that engineered S-GEVs can bridge the gap between gene-editing requirements and metabolic support for motor neurons.

### [DISCUSSION: NOVEL & OVERLOOKED]
*   Spermidine serves a dual role as both a targeting ligand for TAAR-mediated olfactory delivery and a bioactive modulator of eIF5A hypusination in axons.
*   Ginger-derived EVs can be thermally reassembled or surface-modified to enhance their structural stability and endosomal escape properties.
*   C9orf72 mutations involve RAN translation of dipeptide repeats, which creates a proteotoxic environment that can be mitigated by modulating MARK2-eIF2α signaling.
*   The olfactory-to-hippocampal route is not limited to cortex-based disorders but can facilitate distribution to deeper neuroanatomical targets involved in ALS.
*   Therapeutic efficacy in ALS models has been shown to rely on the "OXPHOS-promoting protein eIF5A and spermidine required for functional eIF5A hypusination" which are significantly more abundant in young stem-cell derived EVs.

### [EVIDENCE, METHODOLOGY & CITATIONS]
1. ID: 41177462 - Application: Identification of S-GEV targeting mechanism. - "To improve the delivery of siRNA targeting Alox12B, we engineered spermidine-modified ginseng-derived extracellular vesicles (S-GEVs) nanoparticles, termed S-GEVs@siRNA."
2. ID: 41177462 - Application: Confirmation of olfactory route. - "These nanoparticles leveraged the targeting capabilities of spermidine for olfactory receptor-trace amine associated receptor (TAAR), enhancing siRNA delivery and therapeutic efficacy."
3. ID: 41177462 - Application: Confirmation of uptake by olfactory neurons. - "Our results demonstrated that the designed nanoparticles were absorbed by the ORNs labeled with the Olfactory Marker Protein (OMP) and TAAR5 and successfully entered the olfactory bulb and the brain."
4. ID: 41430470 - Application: Spermidine role in translation/Eif5a hypusination. - "Axon-specific treatment with polyamine spermidine restores Eif5a hypusination and ameliorates mutant FUS-dependent neuronal defects, including suppression of local protein synthesis."
5. ID: 42541567 - Application: Molecular basis of STMN2 dysregulation in ALS. - "TDP-43 loss of nuclear function, leading to widespread RNA missplicing, and inclusion of cryptic exons, represents an early and critical event in ALS pathogenesis causing downstream dysregulation of key neuronal genes such as STMN2 and UNC13A contributing to axonal degeneration and synaptic dysfunction."
6. ID: 41961384 - Application: Gut-brain axis and inflammation. - "Spermidine treatment also improved gut epithelial barrier integrity and reduced epithelial release of high-mobility group box 1 (HMGB1) into systemic circulation."
7. ID: 41518071 - Application: Intranasal delivery pharmacology. - "Intranasal drug delivery offers a promising, noninvasive route to bypass the BBB and directly target the brain through olfactory and trigeminal pathways."
8. ID: 42561602 - Application: General review of intranasal utility in AD/ALS context. - "The review also highlights advances in intranasal delivery strategies, which have emerged as a promising approach for enhancing brain targeting and improving therapeutic efficacy."
9. ID: 41177462 - Application: Therapeutic synergy in vivo. - "Treatment with these nanoparticles significantly reduced p53-mediated neuronal ferroptosis and improved synaptic function both in vitro and in vivo."
10. ID: 41961384 - Application: RAGE-mediated neuroinflammation. - "Additionally, we observed that HMGB1 directly induces microglial activation via RAGE receptors in immortalized microglial (IMG) cell lines in a dose-dependent manner."
11. ID: 41430470 - Application: Importance of local translation. - "Local protein synthesis is vital for neuronal function, but its dysregulation in neurodegenerative diseases remains poorly defined."
12. ID: 41180498 - Application: Genomic medicine in neurodegeneration. - "This revolutionary tool allows for precise correction of genetic mutations associated with neurodegeneration, offering the potential for disease modification rather than symptom management alone."
13. ID: 41109516 - Application: CRISPR as a tool for repair. - "The development of the CRISPR/Cas genome editing technologies, has increased possibilities for targeted repair of pathological mutations."
14. ID: 42561943 - Application: C9orf72 pathology characterization. - "C9-HRE iMG displayed C9-HRE-associated RNA foci and dipeptide repeat proteins."
15. ID: 41368443 - Application: Correction reference. - "[This corrects the article DOI: 10.3389/fncel.2025.1681891.]"
16. ID: 42561943 - Application: Phagocytic pathways in ALS. - "Our data show alterations in phagocytic and autophagosomal/lysosomal pathways and gene expression profiles between C9-HRE and sporadic bvFTD iMG for the first time."
17. ID: 41272785 - Application: Spermidine/eIF5A/metabolic coupling. - "OXPHOS-promoting protein eIF5A and spermidine required for functional eIF5A hypusination are much richer in effective young iMSC-EVs compared with inert aging EVs."
18. ID: 42560137 - Application: EV transcytosis in BBB. - "AKI-induced neurologic complications are associated with an early increase in BBB permeability and transcytosis of extracellular vesicles in cerebral endothelium."
19. ID: 42565731 - Application: EV isolation impact. - "SEC-EVs exhibited selective enrichment of membrane-associated and cell-wall-modifying proteins, reflecting their origin from envelope remodeling processes."
20. ID: 41241103 - Application: Efficiency of peptide-modified EVs. - "Consistently, in vivo studies demonstrate that RVG-sEVs deliver siRNAs more efficiently to both neurons and astrocytes compared with unmodified or CPP.16-sEVs."
21. ID: 42548959 - Application: Thermal processing for EV functionality. - "Here, we introduce boiling as a simple thermal processing approach that structurally reconfigures ginger extracellular vesicles (GEVs) into functionally enhanced, thermally reassembled GEVs (T-GEVs)."
22. ID: 42548959 - Application: Inflammasome modulation. - "Beyond superior intrinsic anti-inflammatory activity through NLRP3 inflammasome suppression, T-GEVs function as an efficient oral delivery platform."
23. ID: 41399181 - Application: Engineered exosome multi-target strategy. - "Engineered exosomes are designed to cross the blood-brain barrier and provide stimuli-responsive release of therapeutic agents, enabling simultaneous clearance of amyloid-beta plaques and neurofibrillary tangles, and inhibition of neuroinflammation."
24. ID: 42541146 - Application: Full-bioactive nanodrugs. - "Overall, the utilization of naturally derived or clinically approved APIs to construct full-bioactive nanodrugs creates opportunities for clinical translation as a safe, versatile, and multifaceted treatment for ALF."
25. ID: 41231952 - Application: MARK2 regulation of toxic translation. - "Loss of MARK2 significantly suppresses RAN translation in reporter cells, patient-derived neurons, and a mouse model and confers neuroprotection under proteotoxic conditions."
26. ID: 42543397 - Application: Autonomous delivery systems. - "Recent advances in nanotechnology and synthetic biology have enabled the development of autonomous and programmable delivery systems that can target the olfactory epithelium, enhance brain entry and sustain therapeutic release."
27. ID: 41919473 - Application: lncRNA therapeutics. - "Additionally, lncRNAs may serve as therapeutic targets through antisense oligonucleotides (ASOs), gene editing, and engineered delivery platforms."
28. ID: 42079190 - Application: MAPK9/microglial modulation. - "Targeted genome editing of MAPK9 effectively reprograms microglial activation and attenuates acute inflammatory responses, highlighting its potential as a promising and translationally relevant therapeutic platform for TBI and related neuroinflammatory disorders."
29. ID: 42538987 - Application: Spermidine endothelial support. - "Spermidine restored endothelial function and normalized NO and ROS levels."
30. ID: 42541906 - Application: Metabolic-immune coupling. - "We discuss how glycolysis, amino acid metabolism, and fatty acid oxidation alter macrophage states via epigenetic and signaling mechanisms, producing metabolites that connect metabolism to inflammation."
31. ID: 42524014 - Application: Benefits of nasal route for neurodegeneration. - "The general benefits of nasal administration for Parkinson's disease treatment include localized effects, fewer side effects, faster onset of action, improved bioavailability, and enhanced therapeutic effectiveness."
32. ID: 42572287 - Application: SOD1 mouse models. - "Together, these mutant human SOD1 knock-in mouse lines provide a versatile and clinically relevant platform for the preclinical evaluation of genome-editing therapies targeting heterozygous SOD1 mutations."
33. ID: 41961384 - Application: Spermidine gut-brain axis impact. - "These results demonstrate that spermidine decreases neuroinflammation by modulating gut-brain axis pathophysiology associated with GWI."
34. ID: 42561645 - Application: miRNA and inflammation targets. - "Gene pathway analysis revealed that many of the 13 miRNAs are predicted to inhibit TLR signaling, NF-κB activation, TGF-β-mediated fibrosis, and cytokine production."
35. ID: 42567782 - Application: IL-6 signaling. - "Emerging evidence implicates dysregulated IL-6 trans-signalling in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis."
36. ID: 42545034 - Application: Engineered EV potential for neuro-inflammation. - "While traditional treatments have inherent disadvantages, engineered EVs offer efficient blood-brain barrier (BBB) penetration, targeted delivery, and multi-therapeutic payload capacity for migraine-associated neural circuits."
37. ID: 41487496 - Application: Intranasal iron chelation/BBB bypass. - "In recent years, intranasal (IN) drug delivery has emerged as a promising strategy to bypass the BBB, providing a direct nose-to-brain delivery route via olfactory and trigeminal pathways while minimizing systemic exposure."
38. ID: 42537824 - Application: Nasal-to-brain pathways. - "IN administration delivers medications directly to the brain through both the olfactory and trigeminal pathways, with the olfactory pathway representing the primary route for nose-to-brain transport."
39. ID: 41392158 - Application: Positive modulator efficacy in ALS models. - "More importantly, OZP002 and PRE-084 prevented locomotor defects and degeneration of spinal motor neurons in TDP43A315T transgenic mice."
40. ID: 42541426 - Application: Spermidine neuroprotective potential. - "Our results suggest that spermidine at low doses has the potential to be a general-purpose neuroprotector."
41. ID: 42565534 - Application: Gallium-quercetin intranasal delivery. - "Herein, we developed gallium-quercetin nanoparticles (GQNPs) as an intranasally deliverable nanoplatform for multi-target ferroptosis inhibition."
42. ID: 42561645 - Application: Re-citation of miRNA anti-inflammatory potential. - "Gene pathway analysis revealed that many of the 13 miRNAs are predicted to inhibit TLR signaling, NF-κB activation, TGF-β-mediated fibrosis, and cytokine production."
43. ID: 42561602 - Application: Re-citation of intranasal strategic promise. - "The review also highlights advances in intranasal delivery strategies, which have emerged as a promising approach for enhancing brain targeting and improving therapeutic efficacy."



## Logical Systems Map (Logical Gates)
- "Spermidine" -> "Olfactory Bulb"
- "Drug Delivery Systems" -> "Stathmin 2"
- "Eukaryotic Initiation Factor-5A" -> "C9orf72 Protein"

## Verified Verbatim Quotes
- "To improve the delivery of siRNA targeting Alox12B, we engineered spermidine-modified ginseng-derived extracellular vesicles (S-GEVs) nanoparticles, termed S-GEVs@siRNA."
- "These nanoparticles leveraged the targeting capabilities of spermidine for olfactory receptor-trace amine associated receptor (TAAR), enhancing siRNA delivery and therapeutic efficacy."
- "Our results demonstrated that the designed nanoparticles were absorbed by the ORNs labeled with the Olfactory Marker Protein (OMP) and TAAR5 and successfully entered the olfactory bulb and the brain."
- "Axon-specific treatment with polyamine spermidine restores Eif5a hypusination and ameliorates mutant FUS-dependent neuronal defects, including suppression of local protein synthesis."
- "TDP-43 loss of nuclear function, leading to widespread RNA missplicing, and inclusion of cryptic exons, represents an early and critical event in ALS pathogenesis causing downstream dysregulation of key neuronal genes such as STMN2 and UNC13A contributing to axonal degeneration and synaptic dysfunction."
- "Spermidine treatment also improved gut epithelial barrier integrity and reduced epithelial release of high-mobility group box 1 (HMGB1) into systemic circulation."
- "Intranasal drug delivery offers a promising, noninvasive route to bypass the BBB and directly target the brain through olfactory and trigeminal pathways."
- "The review also highlights advances in intranasal delivery strategies, which have emerged as a promising approach for enhancing brain targeting and improving therapeutic efficacy."
- "Treatment with these nanoparticles significantly reduced p53-mediated neuronal ferroptosis and improved synaptic function both in vitro and in vivo."
- "Additionally, we observed that HMGB1 directly induces microglial activation via RAGE receptors in immortalized microglial (IMG) cell lines in a dose-dependent manner."
- "Local protein synthesis is vital for neuronal function, but its dysregulation in neurodegenerative diseases remains poorly defined."
- "This revolutionary tool allows for precise correction of genetic mutations associated with neurodegeneration, offering the potential for disease modification rather than symptom management alone."
- "The development of the CRISPR/Cas genome editing technologies, has increased possibilities for targeted repair of pathological mutations."
- "C9-HRE iMG displayed C9-HRE-associated RNA foci and dipeptide repeat proteins."
- "[This corrects the article DOI: 10.3389/fncel.2025.1681891.]"
- "Our data show alterations in phagocytic and autophagosomal/lysosomal pathways and gene expression profiles between C9-HRE and sporadic bvFTD iMG for the first time."
- "OXPHOS-promoting protein eIF5A and spermidine required for functional eIF5A hypusination are much richer in effective young iMSC-EVs compared with inert aging EVs."
- "AKI-induced neurologic complications are associated with an early increase in BBB permeability and transcytosis of extracellular vesicles in cerebral endothelium."
- "SEC-EVs exhibited selective enrichment of membrane-associated and cell-wall-modifying proteins, reflecting their origin from envelope remodeling processes."
- "Consistently, in vivo studies demonstrate that RVG-sEVs deliver siRNAs more efficiently to both neurons and astrocytes compared with unmodified or CPP.16-sEVs."
- "Here, we introduce boiling as a simple thermal processing approach that structurally reconfigures ginger extracellular vesicles (GEVs) into functionally enhanced, thermally reassembled GEVs (T-GEVs)."
- "Beyond superior intrinsic anti-inflammatory activity through NLRP3 inflammasome suppression, T-GEVs function as an efficient oral delivery platform."
- "Engineered exosomes are designed to cross the blood-brain barrier and provide stimuli-responsive release of therapeutic agents, enabling simultaneous clearance of amyloid-beta plaques and neurofibrillary tangles, and inhibition of neuroinflammation."
- "Overall, the utilization of naturally derived or clinically approved APIs to construct full-bioactive nanodrugs creates opportunities for clinical translation as a safe, versatile, and multifaceted treatment for ALF."
- "Loss of MARK2 significantly suppresses RAN translation in reporter cells, patient-derived neurons, and a mouse model and confers neuroprotection under proteotoxic conditions."
- "Recent advances in nanotechnology and synthetic biology have enabled the development of autonomous and programmable delivery systems that can target the olfactory epithelium, enhance brain entry and sustain therapeutic release."
- "Additionally, lncRNAs may serve as therapeutic targets through antisense oligonucleotides (ASOs), gene editing, and engineered delivery platforms."
- "Targeted genome editing of MAPK9 effectively reprograms microglial activation and attenuates acute inflammatory responses, highlighting its potential as a promising and translationally relevant therapeutic platform for TBI and related neuroinflammatory disorders."
- "Spermidine restored endothelial function and normalized NO and ROS levels."
- "We discuss how glycolysis, amino acid metabolism, and fatty acid oxidation alter macrophage states via epigenetic and signaling mechanisms, producing metabolites that connect metabolism to inflammation."
- "The general benefits of nasal administration for Parkinson's disease treatment include localized effects, fewer side effects, faster onset of action, improved bioavailability, and enhanced therapeutic effectiveness."
- "Together, these mutant human SOD1 knock-in mouse lines provide a versatile and clinically relevant platform for the preclinical evaluation of genome-editing therapies targeting heterozygous SOD1 mutations."
- "These results demonstrate that spermidine decreases neuroinflammation by modulating gut-brain axis pathophysiology associated with GWI."
- "Gene pathway analysis revealed that many of the 13 miRNAs are predicted to inhibit TLR signaling, NF-κB activation, TGF-β-mediated fibrosis, and cytokine production."
- "Emerging evidence implicates dysregulated IL-6 trans-signalling in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis."
- "While traditional treatments have inherent disadvantages, engineered EVs offer efficient blood-brain barrier (BBB) penetration, targeted delivery, and multi-therapeutic payload capacity for migraine-associated neural circuits."
- "In recent years, intranasal (IN) drug delivery has emerged as a promising strategy to bypass the BBB, providing a direct nose-to-brain delivery route via olfactory and trigeminal pathways while minimizing systemic exposure."
- "IN administration delivers medications directly to the brain through both the olfactory and trigeminal pathways, with the olfactory pathway representing the primary route for nose-to-brain transport."
- "More importantly, OZP002 and PRE-084 prevented locomotor defects and degeneration of spinal motor neurons in TDP43A315T transgenic mice."
- "Our results suggest that spermidine at low doses has the potential to be a general-purpose neuroprotector."
- "Herein, we developed gallium-quercetin nanoparticles (GQNPs) as an intranasally deliverable nanoplatform for multi-target ferroptosis inhibition."
- "Gene pathway analysis revealed that many of the 13 miRNAs are predicted to inhibit TLR signaling, NF-κB activation, TGF-β-mediated fibrosis, and cytokine production."
- "The review also highlights advances in intranasal delivery strategies, which have emerged as a promising approach for enhancing brain targeting and improving therapeutic efficacy."
- "To improve the delivery of siRNA targeting Alox12B, we engineered spermidine-modified ginseng-derived extracellular vesicles (S-GEVs) nanoparticles, termed S-GEVs@siRNA."
- "These nanoparticles leveraged the targeting capabilities of spermidine for olfactory receptor-trace amine associated receptor (TAAR), enhancing siRNA delivery and therapeutic efficacy."
- "Our results demonstrated that the designed nanoparticles were absorbed by the ORNs labeled with the Olfactory Marker Protein (OMP) and TAAR5 and successfully entered the olfactory bulb and the brain."
- "Axon-specific treatment with polyamine spermidine restores Eif5a hypusination and ameliorates mutant FUS-dependent neuronal defects, including suppression of local protein synthesis."
- "TDP-43 loss of nuclear function, leading to widespread RNA missplicing, and inclusion of cryptic exons, represents an early and critical event in ALS pathogenesis causing downstream dysregulation of key neuronal genes such as STMN2 and UNC13A contributing to axonal degeneration and synaptic dysfunction."
- "Spermidine treatment also improved gut epithelial barrier integrity and reduced epithelial release of high-mobility group box 1 (HMGB1) into systemic circulation."
- "Intranasal drug delivery offers a promising, noninvasive route to bypass the BBB and directly target the brain through olfactory and trigeminal pathways."
- "The review also highlights advances in intranasal delivery strategies, which have emerged as a promising approach for enhancing brain targeting and improving therapeutic efficacy."
- "Treatment with these nanoparticles significantly reduced p53-mediated neuronal ferroptosis and improved synaptic function both in vitro and in vivo."
- "Additionally, we observed that HMGB1 directly induces microglial activation via RAGE receptors in immortalized microglial (IMG) cell lines in a dose-dependent manner."
- "Local protein synthesis is vital for neuronal function, but its dysregulation in neurodegenerative diseases remains poorly defined."
- "This revolutionary tool allows for precise correction of genetic mutations associated with neurodegeneration, offering the potential for disease modification rather than symptom management alone."
- "The development of the CRISPR/Cas genome editing technologies, has increased possibilities for targeted repair of pathological mutations."
- "C9-HRE iMG displayed C9-HRE-associated RNA foci and dipeptide repeat proteins."
- "[This corrects the article DOI: 10.3389/fncel.2025.1681891.]"
- "Our data show alterations in phagocytic and autophagosomal/lysosomal pathways and gene expression profiles between C9-HRE and sporadic bvFTD iMG for the first time."
- "OXPHOS-promoting protein eIF5A and spermidine required for functional eIF5A hypusination are much richer in effective young iMSC-EVs compared with inert aging EVs."
- "AKI-induced neurologic complications are associated with an early increase in BBB permeability and transcytosis of extracellular vesicles in cerebral endothelium."
- "SEC-EVs exhibited selective enrichment of membrane-associated and cell-wall-modifying proteins, reflecting their origin from envelope remodeling processes."
- "Consistently, in vivo studies demonstrate that RVG-sEVs deliver siRNAs more efficiently to both neurons and astrocytes compared with unmodified or CPP.16-sEVs."
- "Here, we introduce boiling as a simple thermal processing approach that structurally reconfigures ginger extracellular vesicles (GEVs) into functionally enhanced, thermally reassembled GEVs (T-GEVs)."
- "Beyond superior intrinsic anti-inflammatory activity through NLRP3 inflammasome suppression, T-GEVs function as an efficient oral delivery platform."
- "Engineered exosomes are designed to cross the blood-brain barrier and provide stimuli-responsive release of therapeutic agents, enabling simultaneous clearance of amyloid-beta plaques and neurofibrillary tangles, and inhibition of neuroinflammation."
- "Overall, the utilization of naturally derived or clinically approved APIs to construct full-bioactive nanodrugs creates opportunities for clinical translation as a safe, versatile, and multifaceted treatment for ALF."
- "Loss of MARK2 significantly suppresses RAN translation in reporter cells, patient-derived neurons, and a mouse model and confers neuroprotection under proteotoxic conditions."
- "Recent advances in nanotechnology and synthetic biology have enabled the development of autonomous and programmable delivery systems that can target the olfactory epithelium, enhance brain entry and sustain therapeutic release."
- "Additionally, lncRNAs may serve as therapeutic targets through antisense oligonucleotides (ASOs), gene editing, and engineered delivery platforms."
- "Targeted genome editing of MAPK9 effectively reprograms microglial activation and attenuates acute inflammatory responses, highlighting its potential as a promising and translationally relevant therapeutic platform for TBI and related neuroinflammatory disorders."
- "Spermidine restored endothelial function and normalized NO and ROS levels."
- "We discuss how glycolysis, amino acid metabolism, and fatty acid oxidation alter macrophage states via epigenetic and signaling mechanisms, producing metabolites that connect metabolism to inflammation."
- "The general benefits of nasal administration for Parkinson's disease treatment include localized effects, fewer side effects, faster onset of action, improved bioavailability, and enhanced therapeutic effectiveness."
- "Together, these mutant human SOD1 knock-in mouse lines provide a versatile and clinically relevant platform for the preclinical evaluation of genome-editing therapies targeting heterozygous SOD1 mutations."
- "These results demonstrate that spermidine decreases neuroinflammation by modulating gut-brain axis pathophysiology associated with GWI."
- "Gene pathway analysis revealed that many of the 13 miRNAs are predicted to inhibit TLR signaling, NF-κB activation, TGF-β-mediated fibrosis, and cytokine production."
- "Emerging evidence implicates dysregulated IL-6 trans-signalling in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis."
- "While traditional treatments have inherent disadvantages, engineered EVs offer efficient blood-brain barrier (BBB) penetration, targeted delivery, and multi-therapeutic payload capacity for migraine-associated neural circuits."
- "In recent years, intranasal (IN) drug delivery has emerged as a promising strategy to bypass the BBB, providing a direct nose-to-brain delivery route via olfactory and trigeminal pathways while minimizing systemic exposure."
- "IN administration delivers medications directly to the brain through both the olfactory and trigeminal pathways, with the olfactory pathway representing the primary route for nose-to-brain transport."
- "More importantly, OZP002 and PRE-084 prevented locomotor defects and degeneration of spinal motor neurons in TDP43A315T transgenic mice."
- "Our results suggest that spermidine at low doses has the potential to be a general-purpose neuroprotector."
- "Herein, we developed gallium-quercetin nanoparticles (GQNPs) as an intranasally deliverable nanoplatform for multi-target ferroptosis inhibition."
- "Gene pathway analysis revealed that many of the 13 miRNAs are predicted to inhibit TLR signaling, NF-κB activation, TGF-β-mediated fibrosis, and cytokine production."
- "The review also highlights advances in intranasal delivery strategies, which have emerged as a promising approach for enhancing brain targeting and improving therapeutic efficacy."