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Cited by 92Nanoparticle-Based Drug DeliveryRNA Interference and Gene DeliveryAdvanced Drug Delivery Systems

Macrophages Offer A Paradigm Switch for CNS Delivery of Therapeutic Proteins

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Klyachko, Natalia L, Haney, Matthew J, Zhao, Yuling, Manickam, Devika S, Mahajan, Vivek, Suresh, Poornima, Hingtgen, Shawn D, Mosley, R Lee +3 more·2014·Nanomedicine
DOI 10.2217/nnm.13.115PMC PMC4025996
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Abstract

AIMS: Active targeted transport of the nanoformulated redox enzyme, catalase, in macrophages attenuates oxidative stress and as such increases survival of dopaminergic neurons in animal models of Parkinson's disease. Optimization of the drug formulation is crucial for the successful delivery in living cells. We demonstrated earlier that packaging of catalase into a polyion complex micelle ('nanozyme') with a synthetic polyelectrolyte block copolymer protected the enzyme against degradation in macrophages and improved therapeutic outcomes. We now report the manufacture of nanozymes with superior structure and therapeutic indices. METHODS: Synthesis, characterization and therapeutic efficacy of optimal cell-based nanoformulations are evaluated. RESULTS: A formulation design for drug carriers typically works to avoid entrapment in monocytes and macrophages focusing on small-sized nanoparticles with a polyethylene glycol corona (to provide a stealth effect). By contrast, the best nanozymes for delivery in macrophages reported in this study have a relatively large size (≈ 200 nm), which resulted in improved loading capacity and release from macrophages. Furthermore, the cross-linking of nanozymes with the excess of a nonbiodegradable linker ensured their low cytotoxicity, and efficient catalase protection in cell carriers. Finally, the 'alternatively activated' macrophage phenotype (M2) utilized in these studies did not promote further inflammation in the brain, resulting in a subtle but statistically significant effect on neuronal regeneration and repair in vivo. CONCLUSION: The optimized cross-linked nanozyme loaded into macrophages reduced neuroinflammatory responses and increased neuronal survival in mice. Importantly, the approach for nanoformulation design for cell-mediated delivery is different from the common requirements for injectable formulations.

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  • Exosomes have been tested in preclinical models for delivering proteins and small RNA across the BBB.

    “In addition, exosomes have also been tested in preclinical models for delivering proteins and small RNA across the BBB (16, 235, 323).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [323]

    The Discussion & conclusion (page unavailable) reports catalase nanozyme incorporation into exosomes and says vesicles released by macrophages may transfer nanozymes to recipient cells, in the context of increased BBB penetration. It does not report exosomes being tested to deliver small RNA across the BBB, or establish that exosomes themselves crossed it. (LLM, conf=0.85)

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Authors
Klyachko, N. L., Haney, M. J., Zhao, Y., Manickam, D. S., Mahajan, V., Suresh, P., Hingtgen, S. D., Mosley, R. L., Gendelman, H. E., Kabanov, A. V., & Batrakova, E. V.
Affiliations
  • Lomonosov Moscow State University (RU)
  • University of Nebraska Medical Center (US)
  • University of North Carolina at Chapel Hill (US)
Corresponding author
Batrakova, Elena V
ORCID
Venue
Nanomedicine
Publisher
Informa UK Limited
Published
2014-07
Volume
9
Issue
9
Pages
1403-1422
ISSN
  • 1743-5889 (ISSN-L)
  • 1748-6963
DOI
10.2217/nnm.13.115
PMC
PMC4025996
OpenAlex
W2008783540
Cited by
92
References
3
Citations by year
2026: 2 · 2025: 3 · 2024: 2 · 2023: 8 · 2022: 11 · 2021: 9 · 2020: 11 · 2019: 5 · 2018: 8 · 2017: 9 · 2016: 13 · 2015: 6 · 2014: 5
FWCI
3.06
Type
journal article
Language
en
Open access
Locations
  • Nanomedicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Aging (R01AG043540)
  • National Institute of Mental Health (P01 MH 64570, P01MH064570)
  • National Institute on Drug Abuse (P01DA028555)
  • National Institute of Neurological Disorders and Stroke (2R37 NS 36126, R37NS036126, P01-NS31492, P01 NS 43985, R01NS070190, R01NS036126, P01NS031492, R01NS057748, P01NS043985, R01NS034239)
  • National Center for Research Resources (P20 RR-15635, RR-021937, P20RR015635, P20RR021937)
Topics
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
Keywords
catalase, nanozymes, polyion complex micelles, macrophages, Parkinson's disease, dopaminergic neurons, oxidative stress, M2 macrophage phenotype, neuroinflammation, cell-mediated drug delivery, crosslinking, nanoparticle size, neuronal regeneration
MeSH terms
Animals, Blood-Brain Barrier, Catalase, Cattle, Cell Line, Chemistry, Pharmaceutical, Cross-Linking Reagents, Drug Carriers, Encephalitis, Enzyme Stability, Macrophage Activation, Macrophages, Male, Mice, Inbred C57BL, Particle Size, Drug Delivery Systems, Nanomedicine, Mice, Nanocapsules

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