CRISPR delivery systems for organ-specific targeting: Advances and challenges

The clustered regularly interspaced short palindromic repeats (CRISPR)/Cas (CRISPR-associated proteins) systems have revolutionized genome editing, yet targeted organ delivery remains a fundamental barrier to clinical translation. This review explores advances in CRISPR delivery technologies, focusing on strategies to overcome anatomical, cellular, and immunological barriers. A comparative analysis of the advantages and limitations of CRISPR formats, including plasmid DNA (pDNA), mRNA, and ribonucleoprotein (RNP) complexes, as well as an analysis of delivery challenges such as biodistribution inefficiency and off-target risks are provided. Emerging solutions, such as physical methods (e.g., microfluidics), engineered viral vectors, and non-viral systems (exosomes, Artificial intelligence (AI) -designed nanoparticles), have been assessed for their organ-targeting potential. Highlighting liver, lung and tumor-specific approaches, the discussion focuses on how the integration of CRISPR tool diversification with biomaterial engineering can address current limitations. Finally, the review underscores the role of AI in optimizing editors and delivery systems while emphasizing persistent hurdles in immunogenicity, specificity, and ethical frameworks. • Diverse CRISPR systems have evolved, including Cas9 and base/prime editors that enable precise genome manipulation. • Physiological barriers limit the efficacy of CRISPR delivery to targeted organs. • Organ-targeted strategies are discussed to overcome biodistribution challenges. • Immune clearance and off-target effects remain hurdles for clinical translation.