Nanotechnology-Driven Gene Editing: Emerging CRISPR-Cas9 Nanocomposite Systems in Oncology

Abstract

The synergies between CRISPR-Cas9 gene editing technology and advanced nanotechnology represent a paradigm shift in precision oncology, however, significant gaps remain between the promise of preclinical research and clinical reality. Although remarkable editing efficiencies (5090) exist in lipid nanoparticles and the FDA has approved hereditary disease treatments, there are fundamental limiting factors to clinical translation in solid tumors, including delivery barriers, heterogeneity of the tumor microenvironment, and immunological constraints. This comprehensive review article discusses nanocomposite delivery systems of CRISPR-Cas9 in cancer therapy, synthesizing evidence from over 100 recent studies on fundamental mechanisms, delivery systems, targeting control, clinical outcomes, safety profiles, and future perspectives. In immunogenic cancers, clinical trials of CRISPR-editing tumor-infiltrating lymphocytes have shown encouraging objective response rates (60%) with durable responses; however, little improvement has been observed in immunologically cold tumors, suggesting that gene editing alone cannot overcome fundamental microenvironmental barriers. The persistent challenges identified through critical analysis include but are not limited to the following: off-target mutation rates (1-15%), pre-existing Cas9 immunity in 65% of the population, the costs of manufacturing it are out of control, manufacturing costs are greater than 400000 per patient and there is lack of long term safety data. Next-generation technologies (base editors, prime editors, and AI-optimal delivery systems) purport to increase the precision of translation incrementally; however, they do not necessarily overcome the fundamental barriers to translational processes. The review highlights that responsible development requires strict criteria of evidence, open disclosures of failures, rational consideration of clinical situations, and clear decision-making frameworks to determine when CRISPR-nanodelivery truly benefits patients versus when conventional therapies are preferable.