Effects of local structural transformation of lipid-like compounds on delivery of messenger RNA

Li, Bin; Luo, Xiao; Deng, Binbin; Giancola, JoLynn B.; McComb, David W.; Schmittgen, Thomas D.; Dong, Yizhou

doi:10.1038/srep22137

Cited by 41 publications

(24 citation statements)

References 34 publications

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“…For example, we showed that amphipathic transporters for siRNA perform best with dodecyl-functionalized lipid blocks compared with the analogous hexyl or ethyl materials (43). Langer and coworkers have used high-throughput methods to find optimal lipid compositions for both cationic polymers (44)(45)(46) and LNPs (16,47,48). Additionally, Tew has shown that the lipid and charge distribution greatly influences siRNA uptake, especially in T lymphocytes (26,49).…”

Section: Significancementioning

confidence: 99%

Enhanced mRNA delivery into lymphocytes enabled by lipid-varied libraries of charge-altering releasable transporters

McKinlay

Benner

Haabeth

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

197

203

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We report a strategy for generating a combinatorial library of oligonucleotide transporters with varied lipid domains and their use in the efficient transfection of lymphocytes with mRNA in vitro and in vivo. This library is based on amphiphilic charge-altering releasable transporters (CARTs) that contain a lipophilic block functionalized with various side-chain lipids and a polycationic α-amino ester mRNA-binding block that undergoes rearrangement to neutral small molecules, resulting in mRNA release. We show that certain binary mixtures of these lipid-varied CARTs provide up to a ninefold enhancement in mRNA translation in lymphocytes in vitro relative to either a single-lipid CART component alone or the commercial reagent Lipofectamine 2000, corresponding to a striking increase in percent transfection from 9-12% to 80%. Informed by the results with binary mixtures, we further show that CARTs consisting of optimized ratios of the two lead lipids incorporated into a single hybrid-lipid transporter molecule maintain the same delivery efficacy as the noncovalent mixture of two CARTs. The lead lipid CART mixtures and hybrid-lipid CARTs show enhanced lymphocyte transfection in primary T cells and in vivo in mice. This combinatorial approach for rapidly screening mRNA delivery vectors has provided lipid-varied CART mixtures and hybrid-lipid CARTs that exhibit significant improvement in mRNA delivery to lymphocytes, a finding of potentially broad value in research and clinical applications.

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Section: Significancementioning

confidence: 99%

Enhanced mRNA delivery into lymphocytes enabled by lipid-varied libraries of charge-altering releasable transporters

McKinlay

Benner

Haabeth

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

197

203

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“…Most recently, Finn et al (2018) reported that lipid nanoparticles were able to co-deliver Cas9 mRNA and chemically modified sgRNA as well, which reduced target protein expression over 1 year. In 2016, Li et al explored the effects of local structural transformation on mRNA delivery by exchanging the positions of hydroxyl and amino groups in a lipid-like compound reported previously (Dong, Eltoukhy, et al, 2014;Li, Luo, Deng, et al, 2016). They found that a minor structural alteration elevated over 10-fold more efficient than that of original counterpart in Hep3B cells, a human hepatoma cell line (Li, Luo, Deng, et al, 2016).…”

Section: Lipid and Lipid-derived Nanoparticles For Mrna Deliverymentioning

confidence: 99%

“…In 2016, Li et al explored the effects of local structural transformation on mRNA delivery by exchanging the positions of hydroxyl and amino groups in a lipid-like compound reported previously (Dong, Eltoukhy, et al, 2014;Li, Luo, Deng, et al, 2016). They found that a minor structural alteration elevated over 10-fold more efficient than that of original counterpart in Hep3B cells, a human hepatoma cell line (Li, Luo, Deng, et al, 2016). In the same year, Turnbull et al (2016) performed a direct intramyocardial injection of C14-113 lipid nanoparticles carrying chemically modified GFP mRNA.…”

Section: Lipid and Lipid-derived Nanoparticles For Mrna Deliverymentioning

confidence: 99%

Nanoscale platforms for messenger RNA delivery

Zhang

Dong

2018

WIREs Nanomed Nanobiotechnol

Self Cite

141

142

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Messenger RNA (mRNA) has become a promising class of drugs for diverse therapeutic applications in the past few years. A series of clinical trials are ongoing or will be initiated in the near future for the treatment of a variety of diseases. Currently, mRNA-based therapeutics mainly focuses on ex vivo transfection and local administration in clinical studies. Efficient and safe delivery of therapeutically relevant mRNAs remains one of the major challenges for their broad applications in humans. Thus, effective delivery systems are urgently needed to overcome this limitation. In recent years, numerous nanoscale biomaterials have been constructed for mRNA delivery in order to protect mRNA from extracellular degradation and facilitate endosomal escape after cellular uptake. Nanoscale platforms have expanded the feasibility of mRNA-based therapeutics, and enabled its potential applications to protein replacement therapy, cancer immunotherapy, therapeutic vaccines, regenerative medicine, and genome editing. This review focuses on recent advances, challenges, and future directions in nanoscale platforms designed for mRNA delivery, including lipid and lipid-derived nanoparticles, polymer-based nanoparticles, protein derivatives mRNA complexes, and other types of nanomaterials. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Biology-Inspired Nanomaterials > Lipid-Based Structures Biology-Inspired Nanomaterials > Nucleic Acid-Based Structures.

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“…Further, these authors prepared optimized TNT‐b 10 LLNs (O‐TNT‐b 10 LLNs) using TNT‐b 10 /DOPE/Chol/DMG‐PEG2000 = 30/40/35/0.75 and showed that this formulation was stable up to 4 weeks and exhibited tenfold higher mRNA delivery efficiency compared to TNT‐a 10 LLNs formulated under the same condition. More importantly, O‐TNT‐b 10 LLNs delivered mRNA specifically to spleen after intravenous and intraperitoneal injection, but not after subcutaneous injection in mice …”

Section: Nanocarriersmentioning

confidence: 99%

Organic Nanocarriers for Delivery and Targeting of Therapeutic Agents for Cancer Treatment

Peng

Bariwal

Kumar

et al. 2020

Advanced Therapeutics

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Nanocarriers have the capability to deliver a variety of drugs to disease sites. Different biological barriers prevent the successful delivery of nanoformulations to target sites, thereby limiting effective therapeutic response. Although numerous efforts have been made to design novel nanocarriers by incorporating various functionalities to get better therapies, most strategies have failed to translate drug delivery systems to the clinic. Impediments such as the incapability to hold drugs stably in nanocarriers during circulation, non‐specific distribution, and inadequate delivery of therapeutic agents to target sites due to complex tumor microenvironment remain a challenge. Herein, different organic polymer and lipid‐based nanocarriers and their encouraging therapeutic effectiveness to treat cancer are discussed. Recent development in multifunctional and stimuli sensitive nanocarriers is also highlighted. Finally, the challenges and innovative strategies to overcome various obstacles and limitations for their successful translation into the clinic are discussed.

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Effects of local structural transformation of lipid-like compounds on delivery of messenger RNA

Cited by 41 publications

References 34 publications

Enhanced mRNA delivery into lymphocytes enabled by lipid-varied libraries of charge-altering releasable transporters

Enhanced mRNA delivery into lymphocytes enabled by lipid-varied libraries of charge-altering releasable transporters

Nanoscale platforms for messenger RNA delivery

Organic Nanocarriers for Delivery and Targeting of Therapeutic Agents for Cancer Treatment

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