Multimeric RNAs for efficient RNA-based therapeutics and vaccines

Kim, Dajeong; Han, Sangwoo; Ji, Yoonbin; Moon, Sung‐Hyun; Nam, Hyangsu; Lee, Jong Bum

doi:10.1016/j.jconrel.2022.03.052

Cited by 4 publications

(4 citation statements)

References 139 publications

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“…Multimerization was reported as an attractive approach to ensure higher stability in the case of RNA therapeutics . Tetra-branched analogues of bioactive neuropeptides exhibited better stability to protease activity and a higher half-life than their monomeric counterparts .…”

Section: Resultsmentioning

confidence: 99%

“…Various examples have highlighted better in vivo stability and therapeutic efficiency through a sustained action over monomeric molecules. This approach has been successfully used to optimize the biological efficiency of peptides, nucleic acids, or therapeutic antibodies, but no examples are reported concerning simple nucleoside derivatives. If dendrimers have recently been the subject of much interest in medicine, serious challenges remain for their design, large-scale synthesis, characterization, and formulation .…”

Section: Introductionmentioning

confidence: 99%

“…Regarding future therapeutic developments, multimerization appeared to be an effective strategy to enhance drug delivery or biological activity with a lower global concentration . Various examples have highlighted better in vivo stability and therapeutic efficiency through a sustained action over monomeric molecules. This approach has been successfully used to optimize the biological efficiency of peptides, nucleic acids, or therapeutic antibodies, but no examples are reported concerning simple nucleoside derivatives.…”

Section: Introductionmentioning

confidence: 99%

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Modulating Lysosomal pH through Innovative Multimerized Succinic Acid-Based Nucleolipid Derivatives

et al. 2023

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The multimerization of active compounds has emerged as a successful approach, mainly to address the multivalency of numerous biological targets. Regarding the pharmaceutical prospect, carrying several active ingredient units on the same synthetic scaffold was a practical approach to enhance drug delivery or biological activity with a lower global concentration. Various examples have highlighted better in vivo stability and therapeutic efficiency through sustained action over monomeric molecules. The synthesis strategy aims to covalently connect biologically active monomers to a central core using simple and efficient reaction steps. Despite extensive studies reporting carbohydrate or even peptide multimerization developed for therapeutic activities, very few are concerned with nucleic acid derivatives. In the context of our efforts to build non-viral nucleolipid (NL)-based nanocarriers to restore lysosomal acidification defects, we report here a straightforward synthesis of tetrameric NLs, designed as prodrugs that are able to release no more than one but four biocompatible succinic acid units. The use of oil-in-water nanoemulsion-type vehicles allowed the development of lipid nanosystems crossing the membranes of human neuroblastoma cells. Biological evaluations have proved the effective release of the acid within the lysosome of a genetic and cellular model of Parkinson’s disease through the recovery of an optimal lysosomal pH associated with a remarkably fourfold lower concentration of active ingredients than with the corresponding monomers. Overall, these results suggest the feasibility, the therapeutic opportunity, and the better tolerance of multimeric compounds compared to only monomer molecules.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Modulating Lysosomal pH through Innovative Multimerized Succinic Acid-Based Nucleolipid Derivatives

et al. 2023

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“…CRISPR–Cas9 represents a revolutionary gene editing technology. − Multigene editing utilizing the CRISPR/Cas9 system is a crucial tool in treating complex diseases that are governed by multiple genes. − The mRNA form of CRISPR-Cas9 is an ideal candidate for in vivo genome editing due to the advantages of no risk of genome integration, high gene editing efficiency and transient transfection. − However, when trying to achieve efficient multigene editing, the delivery system needs adequate capacity to transfect all RNA species (Cas9 mRNA and multiple small guide RNA) at the required stoichiometry into the cytosol of each individual cell. ,− To date, multisite gene editing using mRNA-based CRISPR/Cas9 continues to face considerable challenges due to the relatively low RNA loading capacity of lipid nanoparticle (LNP) and the preferential encapsulation for low-molecular-weight RNA. ,,− Besides, the undesired liver accumulation of LNPs limited its in vivo application. − Therefore, there is an urgent need to develop an all-in-one vehicle with increased RNA loading capacity, improved stability, and the ability to target different organs for in vivo multilocus gene editing. , …”

mentioning

confidence: 99%

Biomimetic Mineralized CRISPR/Cas RNA Nanoparticles for Efficient Tumor-Specific Multiplex Gene Editing

Liang

Zhang

et al. 2023

ACS Nano

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CRISPR/Cas9 systems have great potential to achieve sophisticated gene therapy and cell engineering by editing multiple genomic loci. However, to achieve efficient multiplex gene editing, the delivery system needs adequate capacity to transfect all CRISPR/Cas9 RNA species at the required stoichiometry into the cytosol of each individual cell. Herein, inspired by biomineralization in nature, we develop an all-in-one biomimetic mineralized CRISPR/Cas9 RNA delivery system. This system allows for precise control over the coencapsulation ratio between Cas9 mRNA and multiple sgRNAs, while also exhibiting a high RNA loading capacity. In addition, it enhances the storage stability of RNA at 4 °C for up to one month, and the surface of the nanoparticles can be easily functionalized for precise targeting of RNA nanoparticles in vivo at nonliver sites. Based on the above characteristics, as a proof-of-concept, our system was able to achieve significant gene-editing at each target gene (Survivin: 31.9%, PLK1: 24.41%, HPV: 23.2%) and promote apoptosis of HeLa cells in the mouse model, inhibiting tumor growth without obvious off-target effects in liver tissue. This system addresses various challenges associated with multicomponent RNA delivery in vivo, providing an innovative strategy for the RNA-based CRISPR/Cas9 gene editing.

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