Aptamer‐Guided CRISPR Systems Delivery: Precision Targeting Strategies, Translational Barriers, and Therapeutic Potential

ABSTRACT The CRISPR system has revolutionized genome editing due to its capability to modify genetic material with precision, programmability, and potential for treating disorders, cancers, and autoimmune diseases. Its use in the clinic is constrained by delivery inefficiencies, off‐target effects, and immunogenicity. Aptamers have been touted as a solution to overcoming these constraints, as they are short, single‐stranded nucleic acids that possess high specificity and affinity for cellular targets. This review highlights the convergence of aptamer technology and CRISPR‐Cas9 delivery, with the focus on conjugation chemistries to engineer targeted delivery systems. This review discusses various aptamer‐functionalized platforms, including lipid nanoparticles, polymeric carriers, gold nanoparticles, and DNA/RNA nanostructures, and their potential for cellular uptake, endosomal release, and site‐specific genome editing. Therapeutic uses in cancer gene editing, immune cell engineering, and gene correction of genetic diseases are discussed, along with the translational hurdles, including aptamer and CRISPR components stability, immunogenicity, off‐targeting, and manufacturing. Finally, future directions include the combination of aptamer‐directed systems with next‐generation genome sequencing, artificial intelligence‐aided aptamer design, and addressing the regulatory challenges associated with clinical use. By leveraging the molecular selectivity of aptamers, this strategy could lead to a family of safe, efficacious, and targeted gene therapeutics.