Advances and Challenges of Stimuli-Responsive Nucleic Acids Delivery System in Gene Therapy

Abstract

Gene therapy has emerged as a powerful tool to treat various diseases, such as cardiovascular diseases, neurological diseases, ocular diseases and cancer diseases. In 2018, the FDA approved Patisiran (the siRNA therapeutic) for treating amyloidosis. Compared with traditional drugs, gene therapy can directly correct the disease-related genes at the genetic level, which guarantees a sustained effect. However, nucleic acids are unstable in circulation and have short half-lives. They cannot pass through biological membranes due to their high molecular weight and massive negative charges. To facilitate the delivery of nucleic acids, it is crucial to develop a suitable delivery strategy. The rapid development of delivery systems has brought light to the gene delivery field, which can overcome multiple extracellular and intracellular barriers that prevent the efficient delivery of nucleic acids. Moreover, the emergence of stimuli-responsive delivery systems has made it possible to control the release of nucleic acids in an intelligent manner and to precisely guide the therapeutic nucleic acids to the target site. Considering the unique properties of stimuli-responsive delivery systems, various stimuli-responsive nanocarriers have been developed. For example, taking advantage of the physiological variations of a tumor (pH, redox and enzymes), various biostimuli- or endogenous stimuli-responsive delivery systems have been fabricated to control the gene delivery processes in an intelligent manner. In addition, other external stimuli, such as light, magnetic fields and ultrasound, have also been employed to construct stimuli-responsive nanocarriers. Nevertheless, most stimuli-responsive delivery systems are in the preclinical stage, and some critical issues remain to be solved for advancing the clinical translation of these nanocarriers, such as the unsatisfactory transfection efficiency, safety issues, complexity of manufacturing and off-target effects. The purpose of this review is to elaborate the principles of stimuli-responsive nanocarriers and to emphasize the most influential advances of stimuli-responsive gene delivery systems. Current challenges of their clinical translation and corresponding solutions will also be highlighted, which will accelerate the translation of stimuli-responsive nanocarriers and advance the development of gene therapy.

Functionalized nanoparticles to deliver nucleic acids to the brain for the treatment of Alzheimer’s disease

“…In contrast to conventional drugs, the distinct characteristics of nucleic acids for therapeutic purposes necessitate delivery through vectors. Overall, the effectiveness of nucleic acid therapy heavily depends on the delivery vectors guiding the nucleic acid to the intended target sites (Lin and Qi, 2023).…”

Polymeric-Micelle-Based Delivery Systems for Nucleic Acids

“…ROS tend to increase in many diseases, including tumors [ 73 ]. For example, while the normal ROS value is 0.02 µM, this value can increase to 100 µM in cancer cells [ 74 ]. In such situations, tumor cells increase the production of reducing agents to maintain the balance between ROS production and depletion.…”

“…Enzymes are bioactive substances of critical importance, which catalyze substrates in many biological and metabolic processes in the body [ 75 ]. The dysregulation of enzyme expression and activity indicates a pathological condition [ 74 ]. Changes in enzyme profiles have been associated with many diseases in studies.…”

“…A high amount of ATP is needed to counteract the excessive increase in cell growth and angiogenesis in tumor cells. For this reason, the number of mitochondria increases in tumor cells, and they have a much higher value of ATP than normal cells [ 74 ]. Based on this ATP difference, ATP-responsive PMs can be developed.…”

Research progress in nucleus-targeted tumor therapy

“…89 The development of stimulus-sensitive nanocarriers has successfully fabricated various biostimulus- or endogenous stimulus-responsive delivery systems, which can control the gene delivery process in an intelligent manner and overcome the cascading systemic and intracellular barriers, thus fundamentally changing the landscape of nucleic acid drug delivery. 90,91 In order for nucleic acid drugs to be effective against cancer, therapeutic molecules must be delivered inside the target cell and to specific organelles to function well. 92,93 For effective and safe delivery to cancer cells, nucleic acids must usually be packaged into a vector.…”