Gene therapy is a promising strategy for specific treatment of numerous gene-associated human diseases by intentionally altering the gene expression in pathological cells. A successful clinical application of gene-based therapy depends on an efficient gene delivery system. Many efforts have been attempted to improve the safety and efficiency of gene-based therapies. Nanoparticles have been proved to be the most promising vehicles for clinical gene therapy due to their tunable size, shape, surface, and biological behaviors. In this review, the clinical development of nanoparticles for gene delivery will be particularly highlighted. Several promising candidates, which are closest to clinical applications, will be briefly reviewed. Then, the recent developments of nanoparticles for clinical gene therapy will be identified and summarized. Finally, the development of nanoparticles for clinical gene delivery in future will be prospected.
A facile strategy is developed to construct an ultrasensitive pH triggered charge/size dual-rebound gene delivery system for efficient tumor treatment. The therapeutic gene is complexed by polyethylenimine (PEI) and poly-l-glutamate (PLG), further in situ tightened by aldehyde modified polyethylene glycol (PEG) via Schiff base reaction. The generated Schiff base bonds are stable in neutral pH but cleavable in tumor extracellular pH. This gene delivery system possesses following favorable properties: (1) the tunable gene delivery system is constructed by chemical bench-free "green" and fast process which is favored by clinician, (2) PEG cross-linking shields the surface positive charges and tightens the complex particles, leading to decreased cytotoxicity, improved stability, and prolonged circulation, (3) PEG shielding can be rapidly peeled off by acidic pH as soon as arriving tumors, (4) dual charge/size ultrasensitively rebounding to higher positive potential and bigger size enhances tumor cell uptake efficiency. A series of experiments both in vitro and in vivo are carried out to investigate this gene delivery system in detail. An antiangiogenesis therapeutic gene is carried for the treatment of CT26 tumors in mice, achieving superior antitumor efficacy which is well proved by sufficient biological evidence. The system has great potentials for cancer therapy in the future.
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