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<p>CRISPR-Cas9 is a powerful gene-editing tool for treating genetic diseases and cancer, but effective in vivo delivery remains challenging. Lipid nanoparticles (LNPs) are promising non-viral vectors offering biocompatible, targeted transport of CRISPR components, including plasmid DNA, mRNA, and ribonucleoproteins. Optimizing lipid composition (cationic, neutral, cholesterol, PEGylated lipids), particle size, and surface charge enhances gene delivery efficiency, cellular uptake, and endosomal escape. Therapeutic applications include correcting mutations in cystic fibrosis (CFTR), sickle cell anemia (HBB), and Duchenne muscular dystrophy (DMD), and targeting oncogenes (e.g., TP53, KRAS) for personalized cancer therapy. Additionally, LNPs enable immune cell induction, transcriptional regulation (CRISPRi/a), metabolic control, and overcoming drug resistance limitations. Challenges persist, including achieving tissue-specific delivery beyond the liver, reducing off-target effects, and addressing long-term safety concerns such as hepatotoxicity. Computational modeling tools, like CHRAM, facilitate improved LNP design by simulating RNA-lipid interactions, enhancing stability and release efficiency. Clinical trials (e.g., NTLA-2001, NTLA-2002 by Intellia Therapeutics) demonstrate significant therapeutic potential. Despite regulatory, ethical, and accessibility hurdles, continued advancements in LNP chemistry, rigorous safety evaluations, and interdisciplinary collaboration position LNPs prominently in next-generation precision medicine.</p>

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CRISPR-Cas9-Loaded Lipid Nanoparticles: A Promising Strategy for Targeted Gene Editing and Therapy

  • 期刊论文

  • 发表日期：

    2025年8月2日

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  • Shadi Ebrahimi-Khezrabad,
  • Mohaddeseh Aghdasia,
  • Hadi Zare-Zardini,
  • Hossein Eslami,
  • Fatemeh Eskandari

摘要

CRISPR-Cas9 is a powerful gene-editing tool for treating genetic diseases and cancer, but effective in vivo delivery remains challenging. Lipid nanoparticles (LNPs) are promising non-viral vectors offering biocompatible, targeted transport of CRISPR components, including plasmid DNA, mRNA, and ribonucleoproteins. Optimizing lipid composition (cationic, neutral, cholesterol, PEGylated lipids), particle size, and surface charge enhances gene delivery efficiency, cellular uptake, and endosomal escape. Therapeutic applications include correcting mutations in cystic fibrosis (CFTR), sickle cell anemia (HBB), and Duchenne muscular dystrophy (DMD), and targeting oncogenes (e.g., TP53, KRAS) for personalized cancer therapy. Additionally, LNPs enable immune cell induction, transcriptional regulation (CRISPRi/a), metabolic control, and overcoming drug resistance limitations. Challenges persist, including achieving tissue-specific delivery beyond the liver, reducing off-target effects, and addressing long-term safety concerns such as hepatotoxicity. Computational modeling tools, like CHRAM, facilitate improved LNP design by simulating RNA-lipid interactions, enhancing stability and release efficiency. Clinical trials (e.g., NTLA-2001, NTLA-2002 by Intellia Therapeutics) demonstrate significant therapeutic potential. Despite regulatory, ethical, and accessibility hurdles, continued advancements in LNP chemistry, rigorous safety evaluations, and interdisciplinary collaboration position LNPs prominently in next-generation precision medicine.