The delivery of nucleic acids into target cells remains a critical challenge in modern therapeutics, particularly for treating genetic disorders, cancers, and viral infections. Despite significant advances in understanding cellular pathways, the intracellular delivery of nucleic acid therapeutics—such as antisense oligonucleotides (ASO), siRNA, miRNA, mRNA, and plasmid DNA (pDNA)—is hindered by multiple biological barriers. These include nuclease degradation, opsonization, aggregation, poor membrane permeability, and entrapment within endosomes. To overcome these hurdles, researchers have developed stimuli-responsive nanomaterials that respond to specific intracellular cues, with disulfide-bridged systems emerging as one of the most promising platforms due to their redox sensitivity and biodegradability.
Disulfide bonds are particularly attractive because of the significant difference in redox potential between the extracellular environment (~ -200 mV) and the cytosol (~ -350 mV), especially in diseased cells where glutathione (GSH) levels can be up to 10–100 times higher than in healthy tissues. This gradient enables selective activation of disulfide-based carriers inside target cells, facilitating triggered release of nucleic acid payloads while minimizing premature leakage. The reversible cleavage of disulfide linkages under reducing conditions provides an elegant mechanism for spatiotemporal control, enhancing both safety and efficacy.
This review highlights recent innovations in disulfide-containing materials designed for nucleic acid delivery across diverse platforms. Covalent conjugation strategies involve direct attachment of nucleic acids to functionalized carriers via disulfide linkers. For instance, antisense DNA and siRNA molecules modified with multiple disulfide moieties at their termini demonstrate ultrafast cytosolic delivery within minutes, enabling efficient gene silencing of ApoB—a key regulator of cholesterol metabolism. Similarly, dynamic polyconjugates combine pH-responsive PEG shielding with redox-cleavable disulfide bonds, allowing prolonged circulation followed by targeted intracellular release. These systems have achieved robust silencing of hepatic genes such as apoB and ppara in mouse models.
In nonviral vectors, dendrimers represent a well-studied class of macromolecular carriers. Disulfide-cross-linked second-generation PAMAM dendrimers exhibit significantly enhanced transfection efficiency compared to conventional analogs, while maintaining low cytotoxicity. By incorporating reducible cross-linkers like DSP or cystine, these structures undergo controlled degradation in the cytosol, releasing encapsulated pDNA and enabling high-level expression of reporter genes like eGFP and luciferase. Likewise, disulfide-functionalized poly(amido amine) (PAA) polymers provide tunable buffering capacity and efficient endosomal escape, contributing to improved gene delivery across various cell lines.
Peptide-based systems leverage the cell-penetrating ability of arginine-rich sequences combined with redox-sensitive motifs.MDR1 Antibody Biological Activity Cysteine residues enable self-assembly into stable nanoparticles that dissociate upon exposure to intracellular GSH. For example, stearylated peptides with internal disulfide bonds deliver siRNA efficiently both in vitro and in vivo, achieving potent gene silencing without significant toxicity. Helical polypeptides with disulfide cross-links also show promise in condensing siRNA and promoting its unpackaging in the cytoplasm.
Polymeric systems offer another versatile route. Redox-responsive polyethylenimine (PEI) derivatives, including linear PEIS and disulfide-cross-linked variants, demonstrate superior transfection performance with reduced cytotoxicity. Hyperbranched poly(amino ester)s (PAE) with built-in disulfide units not only enhance nucleic acid condensation but also enable rapid degradation in response to GSH, thereby improving cargo release. Furthermore, amphiphilic block copolymers incorporating disulfide linkages allow noncationic encapsulation of RNA and siRNA, avoiding charge-related toxicity while maintaining high delivery efficiency.SARS-CoV-2 S1 Protein (HEK293)medchemexpress
Lipid-based nanoparticles benefit from structural similarity to natural membranes.PMID:35219030 Redox-sensitive liposomes containing disulfide-spaced phospholipids degrade rapidly in the cytosol, enhancing payload release. Notably, gemini surfactants with disulfide bridges have shown up to threefold higher transfection efficiency than commercial reagents like Lipofectamine 2000. In addition, fusogenic lipids such as DOPE promote membrane fusion, bypassing endosomal entrapment and further boosting delivery success.
Inorganic nanomaterials such as gold nanoparticles (AuNPs) and mesoporous silica nanoparticles (MSNs) have been engineered with disulfide linkages to enable controlled release. AuNPs coated with TAT peptide and hyaluronic acid achieve targeted gene delivery to brain tumors, while MSNs functionalized with redox-labile shells deliver both chemotherapeutic drugs and siRNA simultaneously, resulting in synergistic antitumor effects. Carbon dots and iron oxide nanoparticles also show potential as redox-responsive carriers, although clinical translation remains limited.
Finally, nucleic acid-based nanostructures—such as DNA origami and hydrogels—exploit disulfide chemistry for smart release mechanisms. DNA nanohydrogels with GSH-sensitive junctions selectively deliver therapeutic oligonucleotides to cancer cells, whereas aptamer-conjugated DNA tetrahedra enable targeted co-delivery of siRNA and doxorubicin, overcoming multidrug resistance.
Collectively, disulfide-bridged delivery systems represent a powerful and adaptable strategy for nucleic acid therapeutics. Their ability to respond dynamically to intracellular environments enhances targeting precision, reduces off-target effects, and improves overall therapeutic outcomes. As research continues to refine material design and elucidate mechanistic details, these platforms hold immense potential for advancing clinical applications in gene therapy, regenerative medicine, and personalized oncology.MedChemExpress (MCE) offers a wide range of high-quality research chemicals and biochemicals (novel life-science reagents, reference compounds and natural compounds) for scientific use. We have professionally experienced and friendly staff to meet your needs. We are a competent and trustworthy partner for your research and scientific projects.Related websites: https://www.medchemexpress.com