Lipid nanoparticle-based strategies for extrahepatic delivery of nucleic acid therapies – challenges and opportunities

Journal of Controlled Release, Год журнала: 2024, Номер 370, С. 763 - 772

Опубликована: Май 17, 2024

Язык: Английский

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Enhancing RNA-lipid nanoparticle delivery: Organ- and cell-specificity and barcoding strategies

Journal of Controlled Release, Год журнала: 2024, Номер 375, С. 366 - 388

Опубликована: Сен. 18, 2024

Recent advancements in RNA therapeutics highlight the critical need for precision gene delivery systems that target specific organs and cells. Lipid nanoparticles (LNPs) have emerged as key vectors delivering mRNA siRNA, offering protection against enzymatic degradation, enabling targeted cellular uptake, facilitating cargo release into cytosol. This review discusses development optimization of organ- cell-specific LNPs, focusing on their design, mechanisms action, therapeutic applications. We explore innovations such DNA/RNA barcoding, which facilitates high-throughput screening precise adjustments formulations. address major challenges, including improving endosomal escape, minimizing off-target effects, enhancing efficiencies. Notable clinical trials recent FDA approvals illustrate practical applications future potential LNP-based therapies. Our findings suggest while considerable progress has been made, continued research is essential to resolve existing limitations bridge gap between pre-clinical evaluation safety efficacy therapeutics. highlights dynamic LNP research. It outlines a roadmap RNA-based medicine.

Язык: Английский

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Advanced Delivery Systems for Gene Editing: A Comprehensive Review from the GenE-HumDi COST Action Working group

Molecular Therapy — Nucleic Acids, Год журнала: 2025, Номер 36(1), С. 102457 - 102457

Опубликована: Янв. 18, 2025

Язык: Английский

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Spatial genomics of AAV vectors reveals mechanism of transcriptional crosstalk that enables targeted delivery of large genetic cargo

Nature Biotechnology, Год журнала: 2025, Номер unknown

Опубликована: Март 20, 2025

Abstract Cell-type-specific regulatory elements such as enhancers can direct expression of recombinant adeno-associated viruses (AAVs) to specific cell types, but this approach is limited by the relatively small packaging capacity AAVs. In study, we used spatial genomics show that transcriptional crosstalk between individual AAV genomes provides a general method for cell-type-specific large cargo separating distally acting into second genome. We identified and profiled in carrying 11 different active mouse brain. developed methods identify localize their concatemeric forms cultured cells tissue, demonstrate here dependent upon concatemer formation. Finally, leveraged drive 3.2-kb Cas9 manner with systemically administered engineered AAVs, AAV-delivered, minimally invasive, gene editing wild-type mice recapitulates known disease phenotypes.

Язык: Английский

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Efficient intracellular delivery of CRISPR-Cas9 ribonucleoproteins using dendrimer nanoparticles for robust genomic editing

Nano Today, Год журнала: 2025, Номер 61, С. 102654 - 102654

Опубликована: Янв. 31, 2025

Язык: Английский

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Progress in the Development of N-of-1 Therapy

New England Journal of Medicine, Год журнала: 2025, Номер unknown

Опубликована: Май 15, 2025

Язык: Английский

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RNA delivery systems

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(11)

Опубликована: Март 4, 2024

Due to its small size and lifelong optical transparency, the fish Danionella cerebrum is an emerging model organism in biomedical research. How can this vertebrate under 12 mm length produce sounds over 140 dB? We found that it possesses ...Motion basis of nearly all animal behavior. Evolution has led some extraordinary specializations propulsion mechanisms among invertebrates, including mandibles dracula ant claw pistol shrimp. In contrast, ...

Язык: Английский

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Lipo-Xenopeptide Polyplexes for CRISPR/Cas9 based Gene editing at ultra-low dose

Journal of Controlled Release, Год журнала: 2024, Номер 370, С. 239 - 255

Опубликована: Апрель 27, 2024

Double pH-responsive xenopeptide carriers containing succinoyl tetraethylene pentamine (Stp) and lipo amino fatty acids (LAFs) were evaluated for CRISPR/Cas9 based genome editing. Different carrier topologies, variation of LAF/Stp ratios LAF types as Cas9 mRNA/sgRNA polyplexes screened in three different reporter cell lines using genomic targets (Pcsk9, eGFP, mdx exon 23). One U-shaped bundle (B2)-shaped lipo-xenopeptides exhibiting remarkable efficiencies identified. Genome editing potency top observed at sub-nanomolar EC

Язык: Английский

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Dual pH-responsive CRISPR/Cas9 ribonucleoprotein xenopeptide complexes for genome editing

European Journal of Pharmaceutical Sciences, Год журнала: 2024, Номер 205, С. 106983 - 106983

Опубликована: Дек. 7, 2024

Clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR associated (Cas) protein has been proved as a powerful tool for the treatment of genetic diseases. The Cas9 protein, when combined with single-guide RNA (sgRNA), forms Cas9/sgRNA ribonucleoprotein (RNP) capable targeting and editing genome. However, limited availability effective carriers restricted broader application CRISPR/Cas9 RNP. In this study, we evaluated dual pH-responsive amphiphilic xenopeptides (XPs) delivering These artificial lipo-XPs contain apolar cationizable lipoamino fatty acid (LAF) polar oligoaminoethylene units such succinoyl-tetraethylenepentamine (Stp) in various ratios U-shaped topologies. were screened functional RNP delivery four different reporter cell lines, including Duchenne muscular dystrophy (DMD) exon skipping model. Significantly enhanced cellular uptake into HeLa cells, endosomal disruption gal8-mRuby3 potent genome by several complexes was observed lines 5 nM sgRNA range. Comparing mRNA/sgRNA polyplexes DMD model demonstrated similar splice site high two molecular modalities. Based on these studies, analogues U1 LAF2-Stp LAF4-Stp2 structures deployed, tuning amphiphilicity Stp group replacement six oligoamino acids dmGtp, chGtp, dGtp, Htp, Stt, or GEIPA. most (containing chGtp GEIPA) further gene efficiency EC50 values 1 line. Notably, LAF2-dGtp reached 0.51 even upon serum incubation. Another carrier (LAF4-GEIPA2) complexing donor DNA, facilitated up to 43 % homology-directed repair (HDR) eGFPd2 cells visualized switch from green fluorescent (eGFP) blue (BFP). This study presents system tunable RNP/donor DNA polyplexes, offering an easily applicable strategy editing.

Язык: Английский

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Gene Knockout in the Developing Brain of Wild-Type Rodents by CRISPR In Utero Electroporation

Methods in molecular biology, Год журнала: 2025, Номер unknown, С. 221 - 238

Опубликована: Янв. 1, 2025

Язык: Английский

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