Disulfide Bridging Strategies in Viral and Nonviral Platforms for Nucleic Acid Delivery

Abstract

Self-assembled nanostructures that are sensitive to environmental stimuli are promising nanomaterials for drug delivery. In this class, disulfide-containing redox-sensitive strategies have gained enormous attention because of their wide applicability and simplicity of nanoparticle design. In the context of nucleic acid delivery, numerous disulfide-based materials have been designed by relying on covalent or noncovalent interactions. In this review, we highlight major advances in the design of disulfide-containing materials for nucleic acid encapsulation, including covalent nucleic acid conjugates, viral vectors or virus-like particles, dendrimers, peptides, polymers, lipids, hydrogels, inorganic nanoparticles, and nucleic acid nanostructures. Our discussion will focus on the context of the design of materials and their impact on addressing the current shortcomings in the intracellular delivery of nucleic acids.

Thiol- and Disulfide-Based Stimulus-Responsive Soft Materials and Self-Assembling Systems

“…However, the handful of examples covered here is a minute subset of the literature since disulfide-linked drugs were first approved for human use in the early 2000s [ 12 ]. As shown in Figure 3 , there is a wide variety of disulfide-based drug delivery systems for nucleic acid-based drug delivery [ 10 ]. For more information, please consult reviews by Dutta, Saitoa, Quinn, and Wang [ 10 , 11 , 12 ]; as well as several reviews on redox-responsive [ 9 , 102 , 103 , 104 , 105 ] or multi stimulus-responsive [ 15 ] drug delivery systems, in addition to general reviews on them [ 8 , 79 , 106 ].…”

“… Types of drug delivery systems that rely on the presence of disulfide bonds for the targeted delivery of nucleic acids. Reprinted with permission from [ 10 ]. Copyright (2021) American Chemical Society.…”

“…Chemotherapy employing a drug delivery system can be tuned to release the drug when exposed to the unique chemical environment of a cancer cell; more targeted drug delivery results in fewer side effects [ 3 ]. Figure 3 demonstrates the wide variety of drug delivery systems that rely on disulfide bonds for controlled delivery of nucleic acid therapeutics [ 10 ].…”

“…The reviews of Dutta [ 10 ], Wang [ 11 ], and Saitoa [ 12 ] focus on disulfide-based drug delivery systems. Another notable application is in the field of biomedicine, which merges biological and physiological principles within clinical science.…”

Rational Design of Programmable Monodisperse Semi‐Synthetic Protein Nanomaterials Containing Engineered Disulfide Functionality**

“…[1] One of the most important applications of disulfide containing synthetic molecules or macromolecules is in the field of targeted drug delivery. [2] The highly reducing environment of cytoplasm of a living cell (1-10 mM glutathione (GSH)) compared to the extracellular medium (20-40 μM) is effectively used to design smart drug delivery systems. [3] To date, there are number of research groups working in this area to develop to disulfide containing amphiphilic polymers, [4] inorganic nanoparticles, [5] dendrimers, [6] virus-like particles, [7] peptide nucleic acids [8] and nucleic acid nanostructures.…”