Review maps innovations and challenges in safe, efficient delivery systems for therapeutic genome editing

Therapeutic genome editing, utilizing tools like CRISPR-based systems, zinc-finger nucleases, and transcription activator-like effector nucleases, holds immense promise for treating genetic diseases. Despite breakthroughs in editor technology, clinical translation is severely hampered by the inability to achieve safe, efficient, and tissue-specific delivery. Current standard-of-care often involves viral vectors, primarily adeno-associated viruses (AAVs), which offer durable editing but are limited by restricted cargo capacity, potential immunogenicity, and complex manufacturing processes. This gap in effective delivery systems prevents the widespread application of these powerful genetic therapies.

This review systematically surveys the landscape of current and emerging delivery systems for therapeutic genome editing. It comprehensively contrasts established viral platforms, such as adeno-associated viruses, with nonviral modalities, including ionizable lipid nanoparticles. The authors highlight key innovations across various categories like virus-mimicking nanosystems, cell-derived extracellular vesicles, cell-penetrating peptides, and intelligent-responsive multifunctional scaffolds. The review also examines parallel advances in high-throughput barcoded screening and machine learning for vector optimization, alongside rational chemical modification strategies to improve payload stability and specificity in vivo.

The review identifies that while adeno-associated viruses currently dominate clinical development, their utility is constrained by cargo capacity and immunogenicity. Nonviral platforms, particularly ionizable lipid nanoparticles (LNPs), have demonstrated remarkable efficacy for hepatic targets, with clinical trials reporting up to 93% protein knockdown after a single dose. Emerging modalities like virus-mimicking nanosystems, cell-derived extracellular vesicles, and cell-penetrating peptides are significantly enriching the delivery toolbox. These newer systems support transient expression and programmable targeting across diverse editors and tissues, addressing limitations of traditional vectors. > Parallel advances in high-throughput barcoded screening and machine learning are accelerating the optimization of these delivery vectors, while rational chemical modification of payloads improves their in vivo stability and specificity. This interdisciplinary approach is crucial for overcoming the persistent challenges in clinical translation.