Core Bottlenecks and Optimization Strategies of Delivery Systems for Cancer Gene Therapy: Intracellular Delivery Barriers, Deficient Targeting, and Insufficient Stability

Abstract

Cancer gene therapy can intervene in cancer progression at the genetic level, which is an important innovative direction for tumor treatment. Its clinical application is limited by the safety and efficiency of nucleic acid delivery in the body. With the continuous optimization of related technologies and vectors, the academic circle has made key progress in overcoming in vivo delivery barriers and improving material systems. Nevertheless, existing delivery systems still face key challenges such as the difficulty in balancing efficiency and safety, and insufficient adaptability to the complex in vivo environment. The future development of this field will place greater emphasis on the "programmed" delivery concept, and realize precise regulation of vector stealth in circulation, active recognition at tumor sites, and efficient intracellular release through multidisciplinary collaboration of materials science, nanotechnology, synthetic biology and other disciplines. Focusing on the three core bottlenecks of intracellular delivery barriers, deficient targeting, and insufficient stability, this paper systematically reviews the optimization strategies and research advances in pH-responsive materials, membrane fusion peptides, active targeting ligands, cleavable PEGylation, and engineered exosomes, to provide a reference for the rational design and clinical translation of delivery systems for cancer gene therapy.