The DOI matches its Crossref record; 57 of the 60 references it cites were found in a registry or an index; 20 of the 28 sources its claims cite were checked for support.
Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system
Abstract
The systemic delivery of mRNA molecules to the central nervous system is challenging as they need to cross the blood-brain barrier (BBB) to reach into the brain. Here we design and synthesize 72 BBB-crossing lipids fabricated by conjugating BBB-crossing modules and amino lipids, and use them to assemble BBB-crossing lipid nanoparticles for mRNA delivery. Screening and structure optimization studies resulted in a lead formulation that has substantially higher mRNA delivery efficiency into the brain than those exhibited by FDA-approved lipid nanoparticles. Studies in distinct mouse models show that these BBB-crossing lipid nanoparticles can transfect neurons and astrocytes of the whole brain after intravenous injections, being well tolerated across several dosage regimens. Moreover, these nanoparticles can deliver mRNA to human brain ex vivo samples. Overall, these BBB-crossing lipid nanoparticles deliver mRNA to neurons and astrocytes in broad brain regions, thereby being a promising platform to treat a range of central nervous system diseases.
Overview
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Written from the paper’s full text.
TL;DR
The authors synthesized 72 blood–brain-barrier-crossing lipids and identified MK16 lipid nanoparticles as a lead mRNA delivery platform for the central nervous system. MK16 BLNPs delivered functional mRNA to neurons and astrocytes across broad brain regions in mice and to human brain tissue ex vivo, with efficacy in cocaine-exposure and glioblastoma models.
Key findings
- Screening 72 BBB-crossing lipids across six classes yielded MK16 BLNPs, which produced brain luminescence 8.3-fold greater than MC3 LNPs and 7.4-fold and 6.5-fold higher than ALC-0315 and SM-102 LNPs, respectively.
- After intravenous GFP mRNA delivery at 0.5 mg kg−1, MK16 BLNPs transfected neurons (4.64 ± 1.00% GFP+), astrocytes (6.63 ± 0.62%), BCECs (5.62 ± 0.78%) and microglia (1.68 ± 0.15%); at 1 mg kg−1, these rose to 7.36 ± 0.78%, 9.71 ± 0.70%, 9.18 ± 0.80% and 2.85 ± 0.44%.
- Cre mRNA delivery in Ai14 mice produced tdTomato in hippocampus, thalamus and cortex neurons (5.98 ± 1.52%, 5.86 ± 0.42%, 6.68 ± 1.13%) and astrocytes (8.36 ± 1.85%, 8.49 ± 1.53%, 8.74 ± 2.07%); triple injections increased tdTomato about twofold to 16.7 ± 2.2% in neurons, 19.2 ± 3.0% in astrocytes, 17.9 ± 1.6% in BCECs and 4.5 ± 0.9% in microglia.
- BBB crossing involved caveolae- and γ-secretase-mediated transcytosis; MβCD reduced transcytosis by 43.3 ± 1.7% and MK-0752 by 63.8 ± 3.1%. In orthotopic U-118MG GBM, 70% of MK16 BLNP-Pten mRNA-treated mice survived over 120 days; in human cortical slices ex vivo, ΔFOSB was expressed in 4.00 ± 0.99% of neurons, 6.49 ± 2.33% of astrocytes and 2.38 ± 0.94% of microglia.
Methods
- The authors conjugated BBB-crossing modules to amino lipids to create six classes of BBB-crossing lipids, formulated them with DOPE, cholesterol and DMG-PEG2k, and screened them in N2a and bEnd.3 cells before in vivo testing in C57BL/6J, Ai14 and NU/J mice.
- Main assays included luciferase imaging, flow cytometry of brain cells, immunofluorescence, a bEnd.3 transwell BBB model with endocytosis inhibitors, RNA sequencing, blood biochemistry and histopathology, cocaine-induced conditioned place preference, orthotopic U-118MG GBM treatment, and ex vivo human cortical slice delivery.
- Statistics used one-way ANOVA with Dunnett’s test, two-tailed Student’s t-test, two-way ANOVA with Šidák or Fisher’s LSD post hoc tests, and log-rank Mantel–Cox tests; P < 0.05 was considered significant.
Limitations
- The paper states that future investigational new drug applications require good laboratory practice toxicology studies per FDA guidelines, including dose escalation and repeat administrations to uncover maximum-tolerated dose and potential long-term adverse effects, and that specific mRNA cargoes need careful design and examination.
- Evident from the text: human validation was limited to ex vivo cortical tissue slices from two adult patients with Parkinson’s disease, with no in vivo human delivery or safety data.
- Evident from the text: no statistical method was used to predetermine sample size, and many in vivo experiments used small groups (for example, n = 3 per group).
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Claims the paper makes
74 Own result · 13 Own interpretation · 7 Own method · 6 Partly supported · 4 No basis given · 3 Supported so far · 3 Not supported · 1 Couldn’t confirm · 1 No full text of the sources · accuracy not yet measured
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“d-Serine serves as a neuromodulator and crosses the BBB by amino acid transporter solute carrier family 6 member 14 (refs. 31–35).”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Abstract
What the sources say
- Could not verifycites [31] Hutchinson, K. et al. Describing inhibitor specificity for the amino acid transporter LAT1 from metainference simulations. Biophys. J. 121, 4476–4491 (2022). sourceExperimental — accuracy not yet measured
The Introduction (page not provided) identifies LAT1 as SLC7A5 and says it is abundant at the blood-brain barrier. Searches for d-serine and SLC6A14 found no passage addressing whether d-serine crosses the barrier through SLC6A14. (LLM, conf=0.76)
- Could not verifycites [32] Wolosker, H., Blackshaw, S. & Snyder Solomon, H. Serine racemase: a glial enzyme synthesizing d-serine to regulate glutamate-N-methyl-d-aspartate neurotransmission. Proc. Natl Acad. Sci. USA 96, 13409–13414 (1999). sourceExperimental — accuracy not yet measured
The Discussion describes D-serine as a modulator of NMDA neurotransmission, but does not address its passage across the blood-brain barrier. Searches for blood-brain barrier transport and SLC6A14 found no passage in our copy supporting the claimed transport mechanism. (LLM, conf=0.76)
- Could not verifycites [33] Bodner, O. et al. d-Serine signaling and NMDAR-mediated synaptic plasticity are regulated by system A-type of glutamine/d-serine dual transporters. J. Neurosci. 40, 6489 (2020). sourceExperimental — accuracy not yet measured
The Introduction describes D-serine’s role in synaptic signaling, but does not discuss its passage across the blood–brain barrier. Searches for SLC6A14 and blood–brain barrier transport found no passage establishing the claimed route; the References instead list D-serine transport in the colon and a blood–brain barrier transporter for glutamine. (LLM, conf=0.77)
- Disputedcites [34] Hatanaka, T. et al. Transport of d-serine via the amino acid transporter ATB0,+ expressed in the colon. Biochem. Biophys. Res. Commun. 291, 291–295 (2002). sourceExperimental — accuracy not yet measured
The Results and Discussion identifies ATB0,+ as a transporter involved in intestinal absorption of d-serine, not transport across the blood–brain barrier. It instead attributes d-serine's access to the brain to system L1 (LAT1/4F2hc) at the blood–brain barrier. (LLM, conf=0.91)
Checked by a reasoning model — may be wrong.
- Not checked — no full text of the sourcecites [35] Ganapathy, M. E. & Ganapathy, V. Amino acid transporter ATB0,+ as a delivery system for drugs and prodrugs. Curr. Drug Targets: Immune, Endocr. Metab. Disord. 5, 357–364 (2005). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Could not verify
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“In our prior studies, we found that the increase in ionizable lipid molar ratio in the LNP formulation can augment mRNA delivery44.”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Optimization of BLNPs for systemic mRNA delivery to the brain
What the sources say
- Disputedcites [44] Li, B. et al. An orthogonal array optimization of lipid-like nanoparticles for mRNA delivery in vivo. Nano Lett. 15, 8099–8107 (2015). sourceExperimental — accuracy not yet measured
In the formulation-optimization passage (labeled Abstract; page unavailable), the paper says that reduced levels of the lipid-like component TT3 may facilitate mRNA delivery and describes decreasing its ratio from 40 to 10. It does not report increased delivery from increasing the TT3 ratio; its reported trend runs in the opposite direction. (LLM, conf=0.84)
Checked by a reasoning model — may be wrong.
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Disputed
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“However, the delivery of mRNA to the brain remains a formidable challenge due to the blood–brain barrier (BBB)18,19.”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Abstract
What the sources say
- Not checked — no full text of the sourcecites [18] Xiong, B. et al. Strategies for structural modification of small molecules to improve blood–brain barrier penetration: a recent perspective. J. Med. Chem. 64, 13152–13173 (2021). source
- Partly supportedcites [19] Brown, K. M. et al. Expanding RNAi therapeutics to extrahepatic tissues with lipophilic conjugates. Nat. Biotechnol. 40, 1500–1508 (2022). sourceExperimental — accuracy not yet measured
The Introduction and Discussion (pages unavailable) describe the blood–brain barrier as a challenge for delivering siRNA to the CNS, supporting the general barrier point. The paper addresses siRNA, not mRNA, so it does not establish the claim specifically for mRNA delivery. (LLM, conf=0.86)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Tryptamine derivatives are neurotransmitter precursors that cross the BBB by active transport via Mg2+ and ATP-dependent uptake38–40.”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Abstract
What the sources say
- Partly supportedcites [38] Carbonaro, T. M. & Gatch, M. B. Neuropharmacology of N,N-dimethyltryptamine. Brain Res. Bull. 126, 74–88 (2016). sourceExperimental — accuracy not yet measured
Section 2.2, “Accumulation and storage,” says that DMT crosses the blood–brain barrier by active transport involving Mg2+- and ATP-dependent uptake. It does not establish that this mechanism applies to tryptamine derivatives generally. Section 2.1 describes tryptamine as a precursor to DMT, but does not characterize tryptamine derivatives as neurotransmitter precursors. (LLM, conf=0.88)
- Partly supportedcites [39] Ma, F. et al. Neurotransmitter-derived lipidoids (NT-lipidoids) for enhanced brain delivery through intravenous injection. Sci. Adv. 6, eabb4429 (2020). sourceExperimental — accuracy not yet measured
The Introduction (page unavailable) says that dimethyltryptamine and other tryptamine derivatives have been shown to cross the BBB by active transport. It does not specify Mg2+- or ATP-dependent uptake; searches for those mechanisms found no supporting passage in our copy. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [40] Nagai, F., Nonaka, R. & Satoh Hisashi Kamimura, K. The effects of non-medically used psychoactive drugs on monoamine neurotransmission in rat brain. Eur. J. Pharmacol. 559, 132–137 (2007). source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Specifically, l-DOPA can be recognized by the large neutral amino acids transporter 1 on endothelial cells and be transported across the BBB for the treatment of Parkinson’s disease29–31.”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Abstract
What the sources say
- Partly supportedcites [29] Abbott, A. Levodopa: the story so far. Nature 466, S6–S7 (2010). sourceExperimental — accuracy not yet measured
The opening section (p. 1) describes l-DOPA as a dopamine precursor that crosses the blood-brain barrier to treat Parkinson’s disease. The paper does not identify large neutral amino acid transporter 1 or endothelial cells as the mechanism of transport. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [30] Kageyama, T. et al. The 4F2hc/LAT1 complex transports l-DOPA across the blood–brain barrier. Brain Res. 879, 115–121 (2000). source
- Partly supportedcites [31] Hutchinson, K. et al. Describing inhibitor specificity for the amino acid transporter LAT1 from metainference simulations. Biophys. J. 121, 4476–4491 (2022). sourceExperimental — accuracy not yet measured
The Introduction (page not provided) states that LAT1 is abundant in blood-brain-barrier endothelial cells and mediates levodopa (L-DOPA) transport across the barrier. It does not state that this transport is for treatment of Parkinson’s disease; that treatment detail is not established by the eligible Introduction passages. (LLM, conf=0.78)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“MK-0752 reduces the generation of amyloid-β after crossing the BBB in vivo42,43.”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Abstract
What the sources say
- Supportedcites [42] Cook, J. J. et al. Acute γ-secretase inhibition of nonhuman primate CNS shifts amyloid precursor protein (APP) metabolism from amyloid-β production to alternative APP fragments without amyloid-β rebound. J. Neurosci. 30, 6743–6750 (2010). source
The Results section (page unavailable) identifies MK-0752 as CNS-penetrant, reports its presence in cerebrospinal fluid after oral dosing in rhesus monkeys, and describes reduced generation of newly produced brain amyloid-β. It also reports dose-related reductions in cerebrospinal-fluid Aβ40 and Aβ42. (LLM, conf=0.93)
- Not checked — no full text of the sourcecites [43] Fouladi, M. et al. Phase I trial of MK-0752 in children with refractory CNS malignancies: a pediatric brain tumor consortium study. J. Clin. Oncol. 29, 3529–3534 (2011). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“This increase in preference indicates augmented drug-seeking behaviour in the MK16 BLNP-ΔFosb-treated mice, which is consistent with previous work that overexpressed ΔFOSB selectively in NAc neurons either in inducible transgenic mice or by viral-mediated gene transfer49,52.”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Demonstration of MK16 BLNPs in a cocaine exposure model
What the sources say
- Not checked — no full text of the sourcecites [49] Kelz, M. B. et al. Expression of the transcription factor ΔFosB in the brain controls sensitivity to cocaine. Nature 401, 272–276 (1999). source
- Supportedcites [52] Robison, A. J. et al. Behavioral and structural responses to chronic cocaine require a feedforward loop involving ΔFosB and calcium/calmodulin-dependent protein kinase II in the nucleus accumbens shell. J. Neurosci. 33, 4295–4307 (2013). source
The Introduction (page not available) reports that inducible ΔFosB overexpression in D1-type nucleus accumbens neurons increases rewarding responses to cocaine, including cocaine self-administration. This supports the cited comparison with previous work; the paper does not study the citing authors’ MK16 BLNP-ΔFosb-treated mice. (LLM, conf=0.86)
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“They also presented similar apparent pKa values, with a narrow range from 6.70 to 6.99 (Supplementary Fig. 6d).”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Optimization of BLNPs for systemic mRNA delivery to the brain
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In particular, there was 15.3 ± 0.4% of the MK16 BLNPs in the brain.”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Optimization of BLNPs for systemic mRNA delivery to the brain
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Meanwhile, these BLNPs displayed minimal toxicity in both N2a and bEnd.3 at the tested dose (80% or higher cell viability in all the treated groups; Supplementary Fig. 3a,b).”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Design and development of BLNPs for systemic mRNA delivery to the brain
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Probably not a substantial claim. 14
- It may state two separate claims as one. 27
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“Given that the major clinical problem in addiction is that the user becomes tolerant to the effects of the drug over time, prior studies reported that enhancing ΔFOSB could be a viable approach to treat drug addiction by making subthreshold, non-reinforcing doses of cocaine more reinforcing, potentially reducing the risks of overdose51.”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Demonstration of MK16 BLNPs in a cocaine exposure model
What the sources say
- Disputedcites [51] Zhang, Y. et al. Overexpression of deltaFosB in nucleus accumbens mimics the protective addiction phenotype, but not the protective depression phenotype of environmental enrichment. Front. Behav. Neurosci. 8, 297 (2014). sourceExperimental — accuracy not yet measured
The Results (page unavailable in our copy) say that differences in cocaine intake appeared only at higher doses, not at the low doses the claim says became more reinforcing. The Discussion reports that ΔFosB overexpression in these rats decreased cocaine intake and seeking; it contrasts this with earlier findings of increased sensitivity to low-dose cocaine reward in transgenic mice. The paper does not propose reduced overdose risk through the mechanism claimed. (LLM, conf=0.86)
Checked by a reasoning model — may be wrong.
hedgedconditional- Asserted: fails — The authors may not put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The authors may not put it forward as true. It may state two separate claims as one.
- Disputed
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Temozolomide is an alkylating lipophilic agent that crosses the BBB to treat GBM36,37.”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Abstract
What the sources say
- Partly supportedcites [36] Darlix, A. et al. Chemotherapy and diffuse low-grade gliomas: a survey within the European Low-Grade Glioma Network. Neurooncol. Pract. 6, 264–273 (2019). sourceExperimental — accuracy not yet measured
The Abstract (Conclusions; page unavailable) identifies temozolomide as a chemotherapy drug, and the Discussion (Choice of Chemotherapy Regimen; page unavailable) reports its use and efficacy in diffuse low-grade gliomas. The paper does not establish that it is lipophilic or alkylating, crosses the blood–brain barrier, or is used to treat GBM; those parts of the claim are unsupported by this copy. (LLM, conf=0.85)
- Partly supportedcites [37] de Gooijer, M. C. et al. Improved brain penetration and antitumor efficacy of temozolomide by inhibition of ABCB1 and ABCG2. Neoplasia 20, 710–720 (2018). sourceExperimental — accuracy not yet measured
The Introduction identifies temozolomide as an alkylating agent used in standard GBM treatment and says it penetrates the blood-brain barrier. The Discussion also reports that it readily permeates membranes, but our copy does not establish the specific description “lipophilic.” (LLM, conf=0.86)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Cinnamic derivatives can cross the BBB and insert into the beta sheet of amyloid β proteins41.”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Abstract
What the sources say
- Partly supportedcites [41] Yang, J. et al. Turn-on chemiluminescence probes and dual-amplification of signal for detection of amyloid beta species in vivo. Nat. Commun. 11, 4052 (2020). sourceExperimental — accuracy not yet measured
The Results (In vivo imaging with ADLumin-1; page unavailable) report that ADLumin-1 crossed the blood–brain barrier in mice. The Results (Design and synthesis of ADLumin-1; page unavailable) say its binding moiety has the potential to insert into Aβ beta sheets, but the paper does not identify the probes as cinnamic derivatives or establish insertion as a demonstrated fact. (LLM, conf=0.84)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“An unbiased CPP test was carried out as described52”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Methods > CPP
What the sources say
- Could not verifycites [52] Robison, A. J. et al. Behavioral and structural responses to chronic cocaine require a feedforward loop involving ΔFosB and calcium/calmodulin-dependent protein kinase II in the nucleus accumbens shell. J. Neurosci. 33, 4295–4307 (2013). sourceExperimental — accuracy not yet measured
The Materials and Methods section describes locomotor-response tests (Experiments 2 and 16), but the retrieved passages do not describe an unbiased conditioned place preference (CPP) test. Searches for “CPP,” “place preference,” and an unbiased conditioning protocol did not locate the claimed method in our copy. (LLM, conf=0.74)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Could not verify
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“ΔFOSB is a pivotal transcription factor involved in the regulation of addictive behaviours and the neuropathology of drug dependence49,50.”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Demonstration of MK16 BLNPs in a cocaine exposure model
What the sources say
- Not checked — no full text of the sourcecites [49] Kelz, M. B. et al. Expression of the transcription factor ΔFosB in the brain controls sensitivity to cocaine. Nature 401, 272–276 (1999). source
- Supportedcites [50] Nestler, E. J., Barrot, M. & Self, D. W. ΔFosB: a sustained molecular switch for addiction. Proc. Natl Acad. Sci. USA 98, 11042–11046 (2001). source
The paper’s opening section identifies ΔFosB as a transcription factor whose drug-induced accumulation contributes to lasting brain changes associated with addiction. The section ‘Role of ΔFosB in Behavioral Plasticity to Drugs of Abuse’ reports changes in drug sensitivity and drug-seeking behavior, supporting the claim’s characterization of its role. (LLM, conf=0.91)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“A tumour suppressor gene, like phosphatase and tensin homologue (PTEN), is commonly mutated in wide ranges of GBM, which may be a great candidate for therapeutic intervention27,54.”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Efficacy of MK16 BLNPs for treating GBM
What the sources say
- Partly supportedcites [27] Yang, Z. et al. Large-scale generation of functional mRNA-encapsulating exosomes via cellular nanoporation. Nat. Biomed. Eng. 4, 69–83 (2020). sourceExperimental — accuracy not yet measured
The Results section ('Functional and pharmacokinetic evaluation of CNP generated exosomes'; page not specified) calls PTEN a commonly mutated tumour suppressor gene and tests it as a therapeutic target in two PTEN-deficient glioma models. The in vivo Results report inhibited tumour growth after PTEN-restoring treatment. The copy does not establish how widely PTEN is mutated specifically across GBM. (LLM, conf=0.83)
- Partly supportedcites [54] Hopkins, B. D., Hodakoski, C., Barrows, D., Mense, S. M. & Parsons, R. E. PTEN function: the long and the short of it. Trends Biochem. Sci. 39, 183–190 (2014). sourceExperimental — accuracy not yet measured
The ‘Importance of PTEN function and regulation’ section (page not provided) identifies PTEN as a tumour suppressor frequently lost in cancers including brain tumours and reports mutations across many tumour types. It does not establish how commonly PTEN is mutated specifically in GBM or identify it as a therapeutic candidate for GBM. (LLM, conf=0.85)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The particle sizes of BLNPs ranged from 97.3 ± 2.0 nm to 177.6 ± 2.0 nm with a polydispersity index of <0.3 (Supplementary Fig. 1a,b).”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Design and development of BLNPs for systemic mRNA delivery to the brain
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Using this method, we observed nearly 56.6 ± 2.5% of the MK16 BLNPs in the liver, 6.5 ± 1.1% in the spleen, 7.4 ± 0.8% in the kidneys, 10.5 ± 1.0% in the lungs and 3.7 ± 1.4% in the heart (Supplementary Fig. 10b).”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Optimization of BLNPs for systemic mRNA delivery to the brain
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The MK16 BLNPs exhibited a particle size of 137.0 ± 4.1 nm and an mRNA encapsulation efficiency of approximately 84.8 ± 1.5% (Supplementary Fig. 9a,b).”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Optimization of BLNPs for systemic mRNA delivery to the brain
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Among all the BLNPs tested, MK6 BLNPs induced the highest luminescence intensity in brain tissue 6 h after administration, which was much higher than MC3 LNPs (Fig. 2g,h).”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Design and development of BLNPs for systemic mRNA delivery to the brain
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The particles were positively charged and displayed spherical morphology in cryogenic transmission electron microscopy images (Supplementary Fig. 9c).”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Optimization of BLNPs for systemic mRNA delivery to the brain
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Additionally, MK16 BLNPs showed potent mRNA delivery efficiency in both bEnd.3 cells and N2a cells with negligible cytotoxicity at the tested dose (Supplementary Fig. 9d,e).”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Optimization of BLNPs for systemic mRNA delivery to the brain
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“MK16 BLNPs preferentially delivered GFP mRNA to neurons (4.64 ± 1.00% GFP+), astrocytes (6.63 ± 0.62% GFP+) and brain capillary endothelial cells (BCECs; 5.62 ± 0.78% GFP+) at an mRNA dose of 0.5 mg kg−1, the efficiency of which is particularly superior to those achieved by MC3 LNPs in the corresponding cell types (Fig. 3f,g and Supplementary Fig. 11b).”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Optimization of BLNPs for systemic mRNA delivery to the brain
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Approximately 83.1 ± 2.7% of mRNA was encapsulated in MK6 BLNPs, and they were slightly positively charged (Supplementary Fig. 5c).”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Design and development of BLNPs for systemic mRNA delivery to the brain
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Among this series of MK BLNPs, MK16 BLNPs showed the highest in vivo luminescence intensity in the mouse brain after intravenous injection, which was 1.7-fold higher than MK6E BLNPs and 8.3-fold greater than MC3 LNPs (Fig. 3d,e).”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Optimization of BLNPs for systemic mRNA delivery to the brain
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“MK6 BLNPs were around 139.8 ± 3.5 nm in diameter with a polydispersity index of <0.15 (Supplementary Fig. 5b).”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Design and development of BLNPs for systemic mRNA delivery to the brain
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Additionally, MK16 BLNPs showed 7.4-fold and 6.5-fold higher luminescence intensity than ALC-0315 and SM-102 LNPs in brains after intravenous administration, respectively (Supplementary Fig. 8a,b).”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Optimization of BLNPs for systemic mRNA delivery to the brain
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Substantial levels of fluorescent signals were observed in the brain at the time points of 1 h and 6 h, with no detectable signals at and after the 18 h time point (Supplementary Fig. 10a).”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Optimization of BLNPs for systemic mRNA delivery to the brain
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Quantitative analysis revealed ΔFOSB expression in 4.00 ± 0.99% of neurons, 6.49 ± 2.33% of astrocytes and 2.38 ± 0.94% of microglia, whereas the untreated slices exhibited no detectable expression (Fig. 5e).”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Demonstration of MK16 BLNPs in a cocaine exposure model
plaindirectn = 2- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Moreover, MK16 BLNP-Pten mRNA reduced the tumour growth, thereby achieving prolonged survival in tumour-bearing mice compared with the PBS and MK16 BLNP-control mRNA (mCherry mRNA) groups (Fig. 6b–d).”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Efficacy of MK16 BLNPs for treating GBM
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In PBS-treated mice, tdTomato expression was undetectable 5 days after administration, but on MK16 BLNP delivery of Cre mRNA, a tdTomato signal was observed throughout most regions of the brain, with the strongest signal detected in brain margins (Fig. 4b and Supplementary Fig. 13a,b).”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Delivery applicability and safety studies of MK16 BLNPs
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“mice treated with MK16 BLNP-Pten mRNA showed significantly reduced tumour growth and enhanced survival rates compared with those receiving MC3 LNP-Pten mRNA (Supplementary Fig. 19a–c).”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Efficacy of MK16 BLNPs for treating GBM
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Specifically, in the hippocampus, tdTomato-positive neurons in the MK16 BLNP group accounted for 5.98 ± 1.52% of the total, whereas in the thalamus and cortex, the proportions were 5.86 ± 0.42% and 6.68 ± 1.13%, respectively (Fig. 4f–h).”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Delivery applicability and safety studies of MK16 BLNPs
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Astrocytes with the tdTomato signal represented 8.36 ± 1.85% in the hippocampus, 8.49 ± 1.53% in the thalamus and 8.74 ± 2.07% in the cortex (Fig. 4f–h).”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Delivery applicability and safety studies of MK16 BLNPs
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results suggest that both BBB-crossing modules and diverse structures of amino lipids can greatly affect the in vitro mRNA delivery efficiency.”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Design and development of BLNPs for systemic mRNA delivery to the brain
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Previous studies have reported that several approaches can mediate the crossing of the BBB, including passive diffusion and adsorptive-mediated, carrier-mediated and receptor-mediated transcytosis25.”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Abstract
What the sources say
- Not checked — no full text of the sourcecites [25] Terstappen, G. C., Meyer, A. H., Bell, R. D. & Zhang, W. Strategies for delivering therapeutics across the blood–brain barrier. Nat. Rev. Drug Discov. 20, 362–383 (2021). source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results indicate that MK16 BLNPs can cross endothelial cells by both caveolae- and γ-secretase-mediated transcytosis.”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Mechanisms of MK16 BLNP across the BBB
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“To mitigate any pre-existing bias towards a particular chamber, the groups were carefully balanced.”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Methods > CPP
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All relevant ethical regulations were followed as applicable.”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Methods > Animal studies
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In summary, this BLNP platform represents an important proof-of-concept study to advance LNP-mRNA delivery to the brain, which offers a possible avenue for treating a wide range of brain disorders.”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Outlook
hedged- Asserted: passes — The authors put it forward as true.
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The mice were divided into three random groups: PBS group, control (mCherry) mRNA group and Pten mRNA group.”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Methods > In vivo mRNA delivery for GBM treatment
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All the data met the assumptions of the statistical tests used, including normality and equal variances, and were formally tested to ensure the validity of the statistical analysis.”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Methods > Statistics and reproducibility
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results highlight the biocompatibility and safety of MK16 BLNPs.”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Delivery applicability and safety studies of MK16 BLNPs
plain- Asserted: passes — The authors put it forward as true.
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All research involving human subjects was conducted under STUDY-13–00415 of the Human Research Protection Program at the Icahn School of Medicine at Mount Sinai.”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Methods > Ex vivo mRNA delivery in human brain tissue
plainn = 2- Asserted: passes — The authors put it forward as true.
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“No statistical method was used to predetermine the sample size.”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Methods > Statistics and reproducibility
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The animal experiments conducted in this study adhered to the guidelines approved by the Institutional Animal Care and Use Committee of the Ohio State University (2014A00000106) and the Icahn School of Medicine at Mount Sinai (IPROTO202200000134).”
§ Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system > Methods > Animal studies
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
There is an urgent demand to effectively and safely deliver mRNA to brain cells, especially neurons.
“Despite these significant advances, there is an urgent demand to effectively and safely deliver mRNA to brain cells, especially neurons.”
The authors state this as an assumption.
Conjugating BBB-crossing modules to amino lipids yields BBB-crossing lipids that can facilitate blood–brain barrier crossing of the resulting lipid nanoparticles.
“On the basis of these important findings, we designed and synthesized six classes of BBB-crossing lipids (BLs) by conjugating these molecules with various amino lipids. We hypothesize that these BLs can facilitate formulations of BBB-crossing lipid nanoparticle (BLNP) with mRNA that cross the BBB and efficiently deliver mRNA to the central nervous system (Fig. 1a).”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“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]”
From Lipid Nanoparticles Enhance mRNA Delivery to the Central Nervous System Upon Intrathecal Injection (2025) · cites this paper as [13]
Citations
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Next-generation materials for nucleic acid delivery
van der Meel, R., Wender, P. A., Merkel, O. M., Lostalé‐Seijo, I., Montenegro, J., Miserez, A., Laurent, Q., Sleiman, H. F., & Luciani, P. (2025) · Nature Reviews Materials · doi:10.1038/s41578-025-00814-1 · Cited by 68
“After synthesizing and screening a library of BBB-crossing amino lipids, a lead LNP–mRNA formulation that elicited therapeutic effects in mouse models of cocaine exposure and glioblastoma was established 7 .”
AI-Validated Brain Targeted mRNA Lipid Nanoparticles with Neuronal Tropism
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Metadata
- Authors
- 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, D. D., Wang, L., Guo, K., Cao, D., Yan, J., Deng, B., McComb, D. W., Parsons, R. E., Minier-Toribio, A. M., Holt, L. M., Pan, J., Hashemi, A., Kopell, B. H., Charney, A. W., Nestler, E. J., Peng, P. C., & Dong, Y.
- Affiliations
- Tisch Cancer Institute
- Icahn School of Medicine at Mount Sinai (US)
- The Ohio State University (US)
- Biogen (United States) (US)
- Corresponding author
- Nestler, Eric J.
- Peng, Paul C.
- Dong, Yizhou
- ORCID
- Wang, Chang
- Xue, Yonger
- Markovic, Tamara
- Li, Haoyuan
- Wang, Siyu
- Zhong, Yichen
- Zhang, Yuebao
- Hou, Xucheng
- Yu, Yang
- Liu, Zhengwei
- Tian, Meng
- Wang, Leiming
- Guo, Kaiyuan
- Cao, Dinglingge
- Deng, Binbin
- McComb, David W.
- Parsons, Ramon E.
- Minier-Toribio, Angelica M.
- Holt, Leanne M.
- Hashemi, Alice
- Kopell, Brian H.
- Charney, Alexander W.
- Nestler, Eric J.
- Peng, Paul C.
- Dong, Yizhou
- Venue
- Nature Materials
- Published
- 2025-02-17
- Volume
- 24
- Issue
- 10
- Pages
- 1653-1663
- ISSN
- 1476-1122 (ISSN-L)
- 1476-4660
- PMC
- PMC12514551
- OpenAlex
- W4407661809
- Cited by
- 171
- References
- 60
- Citations by year
- 2026: 106 · 2025: 65
- FWCI
- 42.91
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature Materials (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (R35GM144117)
- U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (P01DA047233)
- 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 › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- blood-brain barrier penetration, lipid nanoparticles, mRNA delivery, central nervous system, intravenous delivery, neuronal transfection, central nervous system disorders
- MeSH terms
- Animals, Astrocytes, Blood-Brain Barrier, Brain, Central Nervous System, Humans, Lipids, Liposomes, Neurons, RNA, Messenger, Mice, Nanoparticles
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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