Whitehead, K. A., Langer, R. & Anderson, D. G. Knocking down barriers: advances in siRNA delivery. Nat. Rev. Drug Discov. 8, 129–138 (2009).
Juliano, R. L., Ming, X. & Nakagawa, O. The chemistry and biology of oligonucleotide conjugates. Acc. Chem. Res. 45, 1067–1076 (2012).
Kole, R., Krainer, A. R. & Altman, S. RNA therapeutics: beyond RNA interference and antisense oligonucleotides. Nat. Rev. Drug Discov. 11, 125–140 (2012).
Dowdy, S. F. Overcoming cellular barriers for RNA therapeutics. Nat. Biotechnol. 35, 222–229 (2017).
Roberts, T. C., Langer, R. & Wood, M. J. A. Advances in oligonucleotide drug delivery. Nat. Rev. Drug Discov. 19, 673–694 (2020).
Wang, S. et al. Accelerating thrombolysis using a precision and clot-penetrating drug delivery strategy by nanoparticle-shelled microbubbles. Sci. Adv. 6, eaaz8204 (2020).
Zhou, Y. et al. Blood–brain barrier-penetrating siRNA nanomedicine for Alzheimer’s disease therapy. Sci. Adv. 6, eabc7031 (2020).
Alterman, J. F. et al. A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system. Nat. Biotechnol. 37, 884–894 (2019).
Nagata, T. et al. Cholesterol-functionalized DNA/RNA heteroduplexes cross the blood–brain barrier and knock down genes in the rodent CNS. Nat. Biotechnol. 39, 1529–1536 (2021).
Brown, K. M. et al. Expanding RNAi therapeutics to extrahepatic tissues with lipophilic conjugates. Nat. Biotechnol. 40, 1500–1508 (2022).
Barker, S. J. et al. Targeting the transferrin receptor to transport antisense oligonucleotides across the mammalian blood–brain barrier. Sci. Transl. Med. 16, eadi2245 (2024).
Miller, T. M. et al. Trial of antisense oligonucleotide tofersen for SOD1 ALS. N. Engl. J. Med. 387, 1099–1110 (2022).
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).
Wu, D. et al. The blood–brain barrier: structure, regulation, and drug delivery. Signal Transduct. Target. Ther. 8, 217 (2023).
Nance, E., Pun, S. H., Saigal, R. & Sellers, D. L. Drug delivery to the central nervous system. Nat. Rev. Mater. 7, 314–331 (2022).
Wang, Y. et al. Overcoming the blood–brain barrier for gene therapy via systemic administration of GSH-responsive silica nanocapsules. Adv. Mater. 35, 2208018 (2023).
Pornnoppadol, G. et al. Bispecific antibody shuttles targeting CD98hc mediate efficient and long-lived brain delivery of IgGs. Cell Chem. Biol. 31, 361–372.e368 (2024).
Kariolis, M. S. et al. Brain delivery of therapeutic proteins using an Fc fragment blood–brain barrier transport vehicle in mice and monkeys. Sci. Transl. Med. 12, eaay1359 (2020).
Dehouck, B. et al. A new function for the LDL receptor: transcytosis of LDL across the blood–brain barrier. J. Cell Biol. 138, 877–889 (1997).
Boado, R. J., Lu, J. Z., Hui, E. K.-W. & Pardridge, W. M. Insulin receptor antibody–sulfamidase fusion protein penetrates the primate blood–brain barrier and reduces glycosoaminoglycans in Sanfilippo type A cells. Mol. Pharm. 11, 2928–2934 (2014).
Tylawsky, D. E. et al. P-selectin-targeted nanocarriers induce active crossing of the blood–brain barrier via caveolin-1-dependent transcytosis. Nat. Mater. 22, 391–399 (2023).
Tian, X. et al. On the shuttling across the blood-brain barrier via tubule formation: mechanism and cargo avidity bias. Sci. Adv. 6, eabc4397 (2020).
Yang, J. et al. Turn-on chemiluminescence probes and dual-amplification of signal for detection of amyloid β species in vivo. Nat. Commun. 11, 4052 (2020).
Carbonaro, T. M. & Gatch, M. B. Neuropharmacology of N,N-dimethyltryptamine. Brain Res. Bull. 126, 74–88 (2016).
Hoffman, L. M. et al. Phase I trial of weekly MK-0752 in children with refractory central nervous system malignancies: a pediatric brain tumor consortium study. Child Nerv. Syst. 31, 1283–1289 (2015).
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).
Bachy, A. et al. SR 57227A: a potent and selective agonist at central and peripheral 5-HT3 receptors in vitro and in vivo. Eur. J. Pharmacol. 237, 299–309 (1993).
Kimberly, W. T. et al. γ-Secretase is a membrane protein complex comprised of presenilin, nicastrin, APH-1, and PEN-2. Proc. Natl Acad. Sci. USA 100, 6382–6387 (2003).
Lu, P. et al. Three-dimensional structure of human γ-secretase. Nature 512, 166–170 (2014).
Bai, X.-C. et al. An atomic structure of human γ-secretase. Nature 525, 212–217 (2015).
Yang, G. et al. Structural basis of γ-secretase inhibition and modulation by small molecule drugs. Cell 184, 521–533(2021).
Zhou, S., Zhou, H., Walian, P. J. & Jap, B. K. Regulation of γ-secretase activity in Alzheimer’s disease. Biochemistry 46, 2553–2563 (2007).
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).
Dovey, H. F. et al. Functional γ-secretase inhibitors reduce β-amyloid peptide levels in brain. J. Neurochem. 76, 173–181 (2001).
Lu, G. et al. Engineered biomimetic nanoparticles achieve targeted delivery and efficient metabolism-based synergistic therapy against glioblastoma. Nat. Commun. 13, 4214 (2022).
Stone, N. L., England, T. J. & O’Sullivan, S. E. A novel transwell blood brain barrier model using primary human cells. Front. Cell. Neurosci. 13, 230 (2019).
Barberio, C. et al. A human-derived neurovascular unit in vitro model to study the effects of cellular cross-talk and soluble factors on barrier integrity. Front. Cell. Neurosci. 16, 1065193 (2022).
Huang, Q. et al. An AAV capsid reprogrammed to bind human transferrin receptor mediates brain-wide gene delivery. Science 384, 1220–1227 (2024).
Ximerakis, M. et al. Single-cell transcriptomic profiling of the aging mouse brain. Nat. Neurosci. 22, 1696–1708 (2019).
Hung, G. et al. Characterization of target mRNA reduction through in situ RNA hybridization in multiple organ systems following systemic antisense treatment in animals. Nucleic Acid Ther. 23, 369–378 (2013).
Li, J. et al. Conservation and divergence of vulnerability and responses to stressors between human and mouse astrocytes. Nat. Commun. 12, 3958 (2021).
Hodge, R. D. et al. Conserved cell types with divergent features in human versus mouse cortex. Nature 573, 61–68 (2019).
Mead, R. J., Shan, N., Reiser, H. J., Marshall, F. & Shaw, P. J. Amyotrophic lateral sclerosis: a neurodegenerative disorder poised for successful therapeutic translation. Nat. Rev. Drug Discov. 22, 185–212 (2023).
Goutman, S. A., Savelieff, M. G., Jang, D.-G., Hur, J. & Feldman, E. L. The amyotrophic lateral sclerosis exposome: recent advances and future directions. Nat. Rev. Neurol. 19, 617–634 (2023).
Gurney, M. E. et al. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 264, 1772–1775 (1994).
Reaume, A. G. et al. Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury. Nat. Genet. 13, 43–47 (1996).
Borel, F. et al. Therapeutic rAAVrh10 mediated SOD1 silencing in adult SOD1G93A mice and nonhuman primates. Hum. Gene Ther. 27, 19–31 (2015).
McCampbell, A. et al. Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models. J. Clin. Invest. 128, 3558–3567 (2018).
Krop, I. et al. Phase I pharmacologic and pharmacodynamic study of the gamma secretase (Notch) inhibitor MK-0752 in adult patients with advanced solid tumors. J. Clin. Oncol. 30, 2307–2313 (2012).
Ran, Y. et al. γ‐secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct. EMBO Mol. Med. 9, 950–966 (2017).
Haapasalo, A. & Kovacs, D. M. The many substrates of presenilin/γ-secretase. J. Alzheimers Dis. 25, 3–28 (2011).
Nair, J. K. et al. Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. J. Am. Chem. Soc. 136, 16958–16961 (2014).
Yu, Y. et al. An RNA-based system to study hepatitis B virus replication and evaluate antivirals. Sci. Adv. 9, eadg6265 (2023).
Nikom, D. & Zheng, S. Alternative splicing in neurodegenerative disease and the promise of RNA therapies. Nat. Rev. Neurosci. 24, 457–473 (2023).
Shi, Y. et al. Chemically modified platforms for better RNA therapeutics. Chem. Rev. 124, 929–1033 (2024).
Scharner, J. & Aznarez, I. Clinical applications of single-stranded oligonucleotides: current landscape of approved and in-development therapeutics. Mol. Ther. 29, 540–554 (2021).
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).
Mummery, C. J. et al. Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer’s disease: a phase 1b, randomized, placebo-controlled trial. Nat. Med. 29, 1437–1447 (2023).
Sarett, S. M. et al. Lipophilic siRNA targets albumin in situ and promotes bioavailability, tumor penetration, and carrier-free gene silencing. Proc. Natl Acad. Sci. USA 114, E6490–E6497 (2017).
Nishina, K. et al. DNA/RNA heteroduplex oligonucleotide for highly efficient gene silencing. Nat. Commun. 6, 7969 (2015).
Asami, Y. et al. Efficient gene suppression by DNA/DNA double-stranded oligonucleotide in vivo. Mol. Ther. 29, 838–847 (2021).
Zou, Y. et al. Blood–brain barrier-penetrating single CRISPR–Cas9 nanocapsules for effective and safe glioblastoma gene therapy. Sci. Adv. 8, eabm8011 (2022).
Hassler, M. R. et al. Comparison of partially and fully chemically-modified siRNA in conjugate-mediated delivery in vivo. Nucleic Acids Res. 46, 2185–2196 (2018).
Ouellette, J. & Lacoste, B. Isolation and functional characterization of primary endothelial cells from mouse cerebral cortex. STAR Protoc. 2, 101019 (2021).