Reactive Oxygen Species-Responsive Drug Delivery Systems

Reactive oxygen species-responsive drug delivery systems exploit elevated levels of reactive oxygen species (ROS) in pathological tissues to achieve spatiotemporally controlled release of therapeutic agents. By incorporating ROS-cleavable linkages—such as boronate esters, thioketal bonds or peroxalate esters—into polymer backbones, micellar cores or prodrug constructs, these carriers remain inert during systemic circulation but undergo rapid structural transformation in oxidative microenvironments. The resulting cleavage triggers cargo release precisely at sites of inflammation, tumours or ischaemia–reperfusion injury. Key platforms include polymeric nanoparticles, core-cross-linked micelles, hydrogels and activatable prodrugs, all engineered to combine biocompatibility, biodegradability and targeting capabilities. Recent advances have extended single-stimulus designs to dual- or multi-stimuli systems that respond to combinations of pH, light or enzymatic activity alongside ROS, enhancing selectivity. Such smart nanomedicines hold global significance for oncology, cardiovascular and inflammatory disorders, offering improved therapeutic indices, reduced off-target toxicity and opportunities for integrated diagnostics and therapy.

Research from Nature Portfolio

Recent studies have demonstrated H₂O₂-sensitive polymer nanoparticles designed for ischaemia–reperfusion therapy. Molecularly engineered peroxalate-based copolymers degrade upon encountering excess hydrogen peroxide, releasing embedded antioxidant monomers that mitigate inflammation and apoptosis in limb and liver models. In parallel, self-immolative boronic ester prodrugs have been developed to scavenge H₂O₂ and liberate antioxidant payloads at oxidative injury sites. These activatable constructs exhibit potent anti-inflammatory and cytoprotective effects in cellular assays and rodent models, while maintaining favourable safety profiles after repeated dosing.

Reactive Oxygen Species-Responsive Drug Delivery Systems publication trend

The graph below shows the total number of articles in reactive oxygen species-responsive drug delivery systems across all publications each year (not limited to Nature Index journals).

Technical terms

Reactive oxygen species (ROS): chemically reactive oxygen-containing molecules generated in metabolism and inflammation.

Stimuli-responsive material: a carrier whose structure and function change upon encountering specific biological triggers.

Nanocarrier: a nanoscale vehicle designed to transport therapeutic agents to target tissues.

Prodrug: an inactive precursor that is converted in situ to the active drug by chemical or enzymatic reactions.

Thioketal linker: an oxidation-sensitive bond that cleaves in the presence of ROS, enabling controlled release.

References

1. Reactive‐Oxygen‐Species‐Responsive Drug Delivery Systems: Promises and Challenges. Advanced Science (2016).
2. H2O2-responsive molecularly engineered polymer nanoparticles as ischemia/reperfusion-targeted nanotherapeutic agents. Scientific Reports (2013).
3. Hydrogen peroxide-activatable antioxidant prodrug as a targeted therapeutic agent for ischemia-reperfusion injury. Scientific Reports (2015).
4. Applications of the ROS-Responsive Thioketal Linker for the Production of Smart Nanomedicines. Polymers (2022).
5. A pH/ROS dual-responsive and targeting nanotherapy for vascular inflammatory diseases. Biomaterials (2019).