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Cited by 34RNA Interference and Gene DeliveryNanoparticle-Based Drug DeliveryAdvanced Drug Delivery Systems

Lipid Nanoparticles Enhance mRNA Delivery to the Central Nervous System Upon Intrathecal Injection

Open access
Xue, Yonger, Wang, Chang, Li, Haoyuan, Du, Shi, Zhong, Yichen, Zhang, Yuebao, Wang, Siyu, Guo, Kaiyuan +13 more·2025·Advanced Materials
DOI 10.1002/adma.202417097PMC PMC12245596
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Abstract

Lipid nanoparticle‐messenger RNA formulations have garnered significant attention for their therapeutic potential in infectious diseases, cancer and genetic disorders. However, effective mRNA delivery to the central nervous system (CNS) remains a formidable challenge. To overcome this limitation, a class of brain‐targeting lipids (BLs) is developed by incorporating brain‐targeting small molecules with amino lipids and formulated them with helper lipids to generate brain‐targeting lipid nanoparticles (BLNPs) for mRNA delivery. Screening studies led to a lead formulation, TD5 BLNPs, outperforming FDA‐approved DLin‐MC3‐DMA LNPs in delivering mRNA to the brain upon intrathecal injection. Specifically, a single intrathecal injection of TD5 BLNP‐GFP mRNA led to GFP expression in 29.6% of neurons and 38.1% of astrocytes across the brain. In an Ai14 mouse model, TD5 BLNP‐Cre recombinase mRNA treatment induced tdTomato expression in ≈30% of neurons and 40% of astrocytes across major brain regions. Notably, delivery of Cas9 mRNA/sgRNA complex using TD5 BLNPs achieved effective genome editing in the brain. Additionally, TD5 BLNPs showed comparable safety profiles to MC3 LNPs, indicating promising biocompatibility. Overall, this TD5 BLNP formulation effectively delivers mRNA to brain tissues via intrathecal injection and facilitates efficient expression in both neurons and astrocytes, presenting a potential strategy for treating CNS diseases.

AI snapshot

Written from the paper’s full text.

TL;DR

A class of brain-targeting lipid nanoparticles (BLNPs) was screened for mRNA delivery, with TD5 BLNPs emerging as the lead formulation for intrathecal delivery to the CNS. TD5 BLNPs outperformed FDA-approved MC3 LNPs in brain mRNA expression, cell-type coverage, CRISPR-Cas9 editing, and showed comparable safety in mice.

Key findings

  • In SH-SY5Y cells, TD5 BLNPs produced a 50.1-fold increase in luminescence intensity relative to MC3 LNPs, and TD5 BLNP-GFP mRNA led to GFP expression in 80.8% ± 1.4% of cells versus 4.4% ± 0.7% for MC3 LNPs.
  • After a single intrathecal injection in mice, TD5 BLNP-GFP mRNA yielded GFP in 29.6% ± 10.7% of neurons, 38.1% ± 6.7% of astrocytes, 12.9% ± 2.2% of microglia, and 26.9% ± 4.3% of brain capillary endothelial cells; MC3 LNPs yielded 6.2% ± 1.2%, 6.3% ± 1.9%, 2.8% ± 0.9%, and 8.8% ± 1.9%, respectively.
  • In Ai14 mice, TD5 BLNP-Cre mRNA induced tdTomato in 34.4% ± 4.0% of hippocampal neurons and 44.8% ± 3.9% of hippocampal astrocytes, with thalamic neurons at 29.5% ± 3.1%, cortical neurons at 31.4% ± 4.1%, thalamic astrocytes at 33.6% ± 6.6%, and cortical astrocytes at 41.0% ± 4.8%.
  • TD5 BLNPs delivering Cas9 mRNA/sgRNA achieved genome editing in multiple brain regions with low tdTomato expression in liver and spleen, and safety markers were comparable to or lower than MC3 LNPs, with inflammatory biomarkers returning to baseline by 24 h and AST, ALT, and BUN within normal ranges.

Methods

  • Six classes of brain-targeting lipids (BLs) were synthesized by coupling brain-targeting small molecules to ionizable lipids, then formulated with cholesterol, DOPE, DMG-PEG2K, and mRNA into BLNPs.
  • Formulations were screened in SH-SY5Y cells for luciferase mRNA delivery and cytotoxicity; TD5 was selected as lead and characterized for size, encapsulation, pKa, uptake pathway, and endosomal escape.
  • In vivo studies used intrathecal injection in mice at an mRNA dose of 0.135 mg/kg, with luminescence imaging, flow cytometry for GFP in brain cell types, Ai14 Cre-recombinase and Cas9/sgRNA editing models, and plasma/histopathology safety assessments.

Limitations

  • The paper states that future clinical translation requires evaluating long-term safety and immune responses associated with repeated intrathecal administration, and investigating mechanisms of off-target distribution to peripheral tissues.
  • The main text states that all methods, materials, and statistical analysis are described in the supporting information, so detailed experimental and statistical methods are not available in the provided text.
  • The in vitro screening relied on SH-SY5Y cells, and the in vivo efficacy and safety data are from mouse models; no human data are reported.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1002/adma.202417097

Cites

46 of 46 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

12 of 14 cited sources checked · 5 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    CSF reaches the entire CNS by exchanging with the interstitial fluid of the CNS parenchyma.

    “By exchanging with the interstitial fluid of the CNS’s parenchyma, CSF reaches the entire CNS, making it an effective route for drug delivery.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [21] a) Householder KT, Dharmaraj S, Sandberg DI, Wechsler-Reya RJ, Sirianni RW, Scientific Reports 2019, 9, 12587; 31467368 PMC6715675 b) Aird RB, Experimental Neurology 1984, 86, 342; 6548450 c) Fowler MJ, Cotter JD, Knight BE, Sevick-Muraca EM, Sandberg DI, Sirianni RW, Advanced Drug Delivery Reviews 2020, 165–166, 77. PMC8182643 32142739 source

      The Discussion (page not provided) says CSF moves around the brain and down the spinal cord, supporting its broad access to the CNS. The non-abstract passages do not establish the claimed exchange with parenchymal interstitial fluid as the means by which it reaches the entire CNS. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
  • Premisecitation

    Compared to intracerebroventricular and intracisternal magna administration, intrathecal injection can generate a broader and more homogeneous distribution of therapeutics throughout the entire brain via CSF circulation.

    “Compared to other CNS injection routes, such as intracerebroventricular (ICV) and intracisternal magna (ICM) administration, IT injection can generate a broader and more homogeneous distribution of therapeutics throughout the entire bran via CSF circulation.[22]”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [22] a) Adank DN, Lunzer MM, Lensing CJ, Wilber SL, Gancarz AM, Haskell-Luevano C, ACS Chemical Neuroscience 2018, 9, 320; 28968061 PMC5821609 b) Bailey RM, Rozenberg A, Gray SJ, Brain Research 2020, 1739, 146832. 32289279 PMC7997047 source

      The Results and Discussion section says that compounds injected intrathecally can reach the brain, citing small amounts detected there after 20 minutes (page unavailable). It does not establish broader or more homogeneous distribution throughout the entire brain than ICV injection, does not compare IT with intracisternal magna injection, and does not attribute the movement to CSF circulation. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Premisecitation

    Intrathecal injection provides direct access to the cerebrospinal fluid (CSF).

    “It provides direct access to the cerebrospinal fluid (CSF), which is generated in the brain ventricles and flows through the subarachnoid space (SAS) surrounding the brain and spinal cord.[21]”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [21] a) Householder KT, Dharmaraj S, Sandberg DI, Wechsler-Reya RJ, Sirianni RW, Scientific Reports 2019, 9, 12587; 31467368 PMC6715675 b) Aird RB, Experimental Neurology 1984, 86, 342; 6548450 c) Fowler MJ, Cotter JD, Knight BE, Sevick-Muraca EM, Sandberg DI, Sirianni RW, Advanced Drug Delivery Reviews 2020, 165–166, 77. PMC8182643 32142739 source
  • Premisecitation

    Six series of brain-targeting lipids (BLs) were previously designed for efficient mRNA delivery to the brain through intravenous administration.

    “We previously designed and developed six series of ionizable lipids referred to as brain-targeting lipids (BLs), for efficient mRNA delivery to the brain through intravenous administration.[13]”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [13] Wang C, Xue Y, Markovic T, Li H, Wang S, Zhong Y, Du S, Zhang Y, Hou X, Yu Y, Liu Z, Tian M, Kang DD, Wang L, Guo K, Cao D, Yan J, Deng B, McComb DW, Parsons RE, Minier-Toribio AM, Holt LM, Pan J, Hashemi A, Kopell BH, Charney AW, Nestler EJ, Peng PC, Dong Y, Nature Materials 2025. PMC12514551 39962245 source
  • Findingown data

    Fourteen BLNPs exhibited at least 5-fold higher mRNA delivery efficiency compared to the FDA-approved MC3 LNP formulation in SH-SY5Y cells.

    “Based on the luminescence intensity measured in SH-SY5Y cells, we found that a series of BLNPs (14 total) exhibited at least 5-fold higher mRNA delivery efficiency compared to the FDA-approved MC3 LNP formulation (Figure. 2a–f).”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 8
  • May combine two claims. 15
  • The quote only partly states this claim. 2

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Tryptamine derivatives function as neurotransmitters.

    “Tryptamine derivatives function as neurotransmitters.[15]”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [15] Carbonaro TM, Gatch MB, Brain Research Bulletin 2016, 126, 74. 27126737 PMC5048497 source

      Section 1.2, “Endogenous roles of DMT” (page unavailable), says DMT may act as a neurotransmitter, but describes its biological role as unestablished. The claim presents neurotransmitter function as established for tryptamine derivatives generally, which this discussion of DMT does not support. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Temozolomide is a lipophilic agent used to treat glioblastoma.

    “Temozolomide is a lipophilic agent to treat glioblastoma.[19]”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [19] Strobel H, Baisch T, Fitzel R, Schilberg K, Siegelin MD, Karpel-Massler G, Debatin KM, Westhoff MA, Biomedicines 2019, 7. 31505812 PMC6783999 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    D-serine is expressed in the mammalian brain and acts as a neuromodulator.

    “D-serine, expressed in the mammalian brain, acts as a neuromodulator.[18]”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [18] Schell MJ, Brady RO Jr., Molliver ME, Snyder SH, Journal of Neuroscience 1997, 17, 1604. 9030620 PMC6573391 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    MK-0752 is a γ-secretase inhibitor that reduces Aβ generation.

    “MK-0752 is a γ-secretase inhibitor to reduce Aβ generation.[16]”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [16] Cook JJ, Wildsmith KR, Gilberto DB, Holahan MA, Kinney GG, Mathers PD, Michener MS, Price EA, Shearman MS, Simon AJ, Wang JX, Wu G, Yarasheski KE, Bateman RJ, Journal of Neuroscience 2010, 30, 6743. 20463236 PMC2913973 source

  • May combine two claims.

    Premisecitation

    Intrathecal injection is less invasive, commonly used in clinical and preclinical settings, and allows repeated dosing with minimal systemic exposure and off-target effects.

    “Moreover, IT injection is less invasive, commonly used in both clinical and preclinical settings, and allows for repeated dosing with minimal systemic exposure and off-target effects.[23]”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [23] Belov V, Appleton J, Levin S, Giffenig P, Durcanova B, Papisov M, Frontiers in Neuroscience 2021, 15, 604197. 33935624 PMC8079755 source

      The Introduction (page unavailable) describes intrathecal lumbar delivery as less invasive than intracerebroventricular delivery, usable for chronic or repeated dosing, and relevant to both clinical and preclinical use. It does not establish minimal systemic exposure or off-target effects; it notes clearance of injected compounds into the blood. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cinnamic acid derivatives bind amyloid beta (Aβ) proteins.

    “Cinnamic acid derivatives are known to bind with amyloid beta (Aβ) proteins.[14]”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [14] Ruwizhi N, Aderibigbe BA, International Journal of Molecular Sciences 2020, 21. 32784935 PMC7460980 source

      Section 5 (page not provided) reports that tacrine–cinnamic acid hybrids inhibited Aβ1–42 aggregation, supporting an effect on amyloid beta. It does not establish that the derivatives bind Aβ proteins; the binding interactions it describes are with cholinesterases. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    TD5 BLNPs may facilitate delivery of mRNAs encoding transcriptional factors to regulate synaptic plasticity and modulate key neurotransmitter systems, thereby mitigating addictive behaviors.

    “Furthermore, TD5 BLNPs may also facilitate delivery of mRNAs encoding transcriptional factors to regulate synaptic plasticity and modulate key neurotransmitter systems, thereby mitigating addictive behaviors.[32]”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [32] Robison AJ, Nestler EJ, Nature Reviews Neuroscience 2011, 12, 623. 21989194 PMC3272277 source

      The ΔFosB subsection (page unavailable) links a transcription factor to cocaine-induced structural plasticity and glutamatergic synaptic function. The paper also discusses gene regulation and addiction-related behavior, but our copy does not address TD5 BLNPs, delivery of transcription-factor mRNAs, or whether such delivery mitigates addictive behavior. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    Efficient uptake of TD5 BLNPs by astrocytes and neurons allows for potent delivery of mRNAs encoding anti-inflammatory proteins, providing a targeted approach to mitigate neuroinflammation in AD and PD.

    “Moreover, the efficient uptake of TD5 BLNPs by astrocytes and neurons allows for potent delivery of mRNAs encoding anti-inflammatory proteins, providing a targeted approach to mitigate neuroinflammation, which is a key contributor to neurodegeneration in both AD and PD.[31]”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [31] Zhang W, Xiao D, Mao Q, Xia H, Signal Transduction and Targeted Therapy 2023, 8, 267. 37433768 PMC10336149 source

      The Immune-directed therapies sections for Alzheimer’s and Parkinson’s disease (page unavailable) support targeting inflammation in both conditions. But our copy does not describe TD5 BLNPs, their uptake by astrocytes or neurons, or delivery of mRNAs encoding anti-inflammatory proteins; searches for TD5, BLNPs, and mRNA delivery found no supporting passage. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    TD5 BLNPs displayed the most efficient mRNA delivery in brain tissues, with luminescence intensity over 42-fold higher than MC3 LNPs.

    “Importantly, TD5 BLNPs displayed the most efficient mRNA delivery in brain tissues, with luminescence intensity over 42-fold higher than MC3 LNPs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    All BLNPs were slightly positively charged and had particle sizes ranging from 97.8 nm ± 3.20 nm to 171.5 nm ± 4.40 nm.

    “All BLNPs were slightly positively charged and particle sizes ranged from 97.8nm ± 3.20nm to 171.5nm ± 4.40nm.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    After IT injection of TD5 BLNP-Cre mRNA into Ai14 mice, injected mRNA distributed throughout the brain with notable accumulation in regions adjacent to brain ventricles.

    “We found distribution of the injected mRNA throughout the brain, with notable accumulation in regions adjacent to the brain ventricles (Figure. 4b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Compared to MC3 LNPs, TD5 BLNPs exhibited a more uniform distribution across the entire brain and achieved significantly higher mRNA delivery efficiency.

    “Compared to MC3 LNPs, TD5 BLNPs exhibited a more uniform distribution across the entire brain and achieved significantly higher mRNA delivery efficiency (Figure. 4c–f).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    29.5% ± 3.1% of neurons in the thalamus exhibited tdTomato signals after TD5 BLNP-Cre mRNA IT injection.

    “In the thalamus and cortex, the percentage of neurons exhibiting tdTomato signals was measured at 29.5% ± 3.1% and 31.4% ± 4.1%, respectively (Figure. 4c–f).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Plasma levels of AST, ALT, and BUN were within normal ranges after TD5 BLNP treatment.

    “To assess potential effects on liver and kidney function, plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and blood urea nitrogen (BUN) were measured and found to be within normal ranges, suggesting no impairment in hepatic or renal function (Figure. 6b–d).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    31.4% ± 4.1% of neurons in the cortex exhibited tdTomato signals after TD5 BLNP-Cre mRNA IT injection.

    “In the thalamus and cortex, the percentage of neurons exhibiting tdTomato signals was measured at 29.5% ± 3.1% and 31.4% ± 4.1%, respectively (Figure. 4c–f).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    TD5 BLNPs entered primary astrocytes mainly through 5-HT1A receptor-mediated endocytosis, with partial involvement of the 5-HT2A receptor.

    “Mal treatment significantly reduced the cellular uptake of TD5 BLNPs in astrocytes by over 50%, whereas Ket caused a slight decrease, suggesting TD5 BNLPs entered primary astrocytes mainly through 5-HT1A receptor-mediated endocytosis, with partial involvement of the 5-HT2A receptor (Figure.3f–g).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    L-DOPA is used in the treatment of Parkinson's disease.

    “L-DOPA is used in the treatment of Parkinson’s disease.[17]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Olanow CW, Agid Y, Mizuno Y, Albanese A, Bonucelli U, Damier P, De Yebenes J, Gershanik O, Guttman M, Grandas F, Movement disorders 2004, 19, 997. 15372588 source

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    TD5 BLNPs hold potential for modulating disease pathways and promoting neuroregeneration in conditions such as Alzheimer's disease and Parkinson's disease.

    “For example, by enabling the delivery of mRNAs encoding neuroprotective proteins or genome-editing tools, TD5 BLNPs hold potential for modulating disease pathways and promoting neuroregeneration in conditions such as Alzheimer’s disease (AD) and Parkinson’s disease (PD).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    TD5 BLNPs effectively target a wide range of brain cell types while maintaining safety and biocompatibility.

    “This LNP formulation effectively targets a wide range of brain cell types while maintaining safety and biocompatibility, making it a promising candidate for future therapeutic applications.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Collectively, TD5 BLNPs offer a highly effective platform for mRNA-based gene therapies, holding great potential for treating a wide range of CNS disorders.

    “Collectively, TD5 BLNPs offer a highly effective platform for mRNA-based gene therapies, holding great potential for treating a wide range of CNS disorders.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    TD5 BLNPs have potential for targeted therapeutic gene editing in the brain with minimal off-target activity.

    “These findings underscore the potential of TD5 BLNPs for targeted therapeutic gene editing in the brain with minimal off-target activity.”
    Quote in the paperSubstantial claim
21 of 21

  • The paper relies on this without support.

    Brain-targeting small molecules incorporated into brain-targeting lipids enhance brain cell uptake of lipid nanoparticles.

    “The brain-targeting small molecules serve as targeting modules to enhance brain cell uptake of LNPs.”
1 of 1

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Authors
Xue, Y., Wang, C., Li, H., Du, S., Zhong, Y., Zhang, Y., Wang, S., Guo, K., Hou, X., Kang, D. D., Liu, Z., Tian, M., Cao, D., Deng, B., McComb, D. W., Markovic, T., Pan, J., Borna, M., Nestler, E. J., Peng, P. C., & Dong, Y.
Affiliations
  • The Ohio State University (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • Biogen (United States) (US)
  • City Therapeutics, Inc. (United States) (US)
  • Tisch Cancer Institute
Corresponding author
  • Nestler, Eric J.
  • Peng, Paul C.
  • Dong, Yizhou
ORCID
Venue
Advanced Materials
Publisher
Wiley
Published
2025-05-03
Volume
37
Issue
27
Pages
e2417097-e2417097
ISSN
  • 0935-9648 (ISSN-L)
  • 1521-4095
DOI
10.1002/adma.202417097
PMC
PMC12245596
OpenAlex
W4410051645
Cited by
34
References
46
Citations by year
2026: 23 · 2025: 11
FWCI
8.53
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Advanced Materials (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
  • National Institute on Drug Abuse (P01DA047233, R01DA040621)
  • National Institute of General Medical Sciences (R35GM144117)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
Keywords
lipid nanoparticles, mRNA delivery, central nervous system, intrathecal administration, helper lipids, Cre recombinase, CRISPR gene editing, neuronal expression, biocompatibility, central nervous system disorders
MeSH terms
Gene Editing, Animals, Astrocytes, Brain, Central Nervous System, Humans, Injections, Spinal, Lipids, Liposomes, Neurons, RNA, Messenger, Mice, Nanoparticles

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