Nano-carrier-based Delivery of CRISPR-Cas9 for Oncolytic Gene Therapy: Insights from Xenograft Models

The CRISPR-Cas9 system has revolutionized genome editing, offering unprecedented precision and efficiency in gene modification. Its potential in cancer therapy, particularly oncolytic gene therapy, has garnered significant attention, especially with the development of advanced delivery platforms. However, effective and safe in vivo delivery of CRISPR components remains a major barrier to clinical translation. This review provides a comprehensive overview of viral and non-viral nanocarrier systems for CRISPR-Cas9 delivery, with a particular focus on their application in xenograft models of cancer. The present study aimed to bridge the gap between molecular innovation and therapeutic application by evaluating the efficiency and safety of CRISPR-Cas9 delivery systems in preclinical oncology models. The mechanisms and classifications of viral vectors, including adeno-associated viruses (AAV), lentivirus, and adenovirus, were emphasized, highlighting their strengths in gene transfer efficiency, while addressing concerns over immunogenicity, genome integration, and scalability. Subsequently, non-viral nanocarriers, including lipid nanoparticles (LNPs), polymeric systems, dendrimers, and metallic nanoparticles, have emerged as safer and more customizable alternatives. Key considerations, including stability, endosomal escape, payload capacity, and tumor targeting, are evaluated, supported by findings from recent xenograft-based studies. A direct comparison between viral and non-viral systems was presented, emphasizing differences in transfection efficiency, biosafety, immunological responses, and gene-editing precision in preclinical tumor models. The clinical relevance of CRISPR-based oncolytic strategies was examined, along with their integration with other cancer therapies. Additionally, the emerging challenges of immune evasion, tumor heterogeneity, and delivery barriers were evaluated. In addition, the regulatory and ethical dimensions surrounding genome editing in cancer therapy are addressed, including long-term safety concerns, germline editing considerations, and global disparities in clinical oversight. The discussion concluded with an examination of future perspectives, highlighting strategic improvements in delivery technologies and validation pipelines. Xenograft models were proposed as a means to accelerate clinical translation.