Research on Rare Genetic Disease Targeted Drug Delivery System Based on CRISPR-Cas9 Technology

The treatment of rare genetic diseases remains a significant challenge, and while CRISPR-Cas9 technology offers a powerful therapeutic pathway, its success is entirely contingent on the development of efficient and safe targeted delivery systems. Current delivery methods are hampered by substantial flaws. Viral vectors, such as AAV, have limited packaging capacity and carry mutation risks, whereas lentiviral vectors pose concerns regarding immunogenicity and carcinogenicity. Meanwhile, non-viral vectors like LNPs suffer from poor targeting specificity, electroporation is restricted to in vitro use, and direct injection is notoriously inefficient. To address these critical limitations, this study investigates three advanced delivery platforms. These include Virus-Like Particles (VLPs), exemplified by the safe and programmable RIDE system with demonstrated efficacy in Huntington’s disease mouse models; smart nanoparticles designed to respond to specific physiological triggers like pH or receptors for precise organ targeting, such as in liver-directed therapy for PH1; and cell-mediated systems utilizing engineered hematopoietic stem cells for diseases like sickle cell anemia. Concurrently, the research tackles persistent issues of targeting precision, immunogenic responses, and editing efficiency through strategic ligand optimization and the application of high-fidelity Cas9 variants. Collectively, this work provides valuable insights and a strategic framework to advance the clinical potential of CRISPR-Cas9 for treating rare genetic diseases.