Ultrasound-Mediated CRISPR Delivery and Sonogenetic Modulation for Precision Therapeutics.

The development of CRISPR-Cas9 technology has transformed gene editing with precise mutations in DNA targeted to treat genetic disorders yet various challenges such as immunogenicity, off-target editing, and lack of temporal control after delivery, making it difficult for therapeutic agents to reach deep tissues like brain, and cardiac tissues. Ultrasound has emerged as a promising solution by influencing sonogenetic modulation and delivery of CRISPR tools in deep tissues for targeted gene editing. Sonogenetic editing has revolutionized the technological advancement of CRISPR-editing and among multiple strategies, ultrasound-mediated delivery of CRISPR systems has enabled non-invasive and controlled genome editing through sonoporation, and upregulation of stimuli-responsive genes. Focused ultrasound combined with microbubbles has demonstrated CRISPR delivery to brain tissue with ∼80% higher efficiency than traditional strategies, allowing precise and advanced treatment of neurodegenerative diseases. In cancer applications, ultrasound has enabled complete tumor eradication via sonodynamic therapy, achieving 64% tumor regression via CAR T-cell therapy. Significant advances in gene therapy for cardiovascular diseases, obesity, and related diseases were also demonstrated recently. Collectively, the review elaborates potential of ultrasound-CRISPR technologies as a powerful tool that enables targeted, and image-guided genetic interventions, capable of advancing the outcomes of gene therapy as a widespread clinical practice.