Redoxcleavable

Redoxcleavable describes bonds or linkers designed to undergo cleavage in response to redox conditions, enabling controlled release of attached cargos. These systems exploit the contrast between extracellular oxidative environments and intracellular reducing spaces, notably the high cytosolic concentration of glutathione. Redoxcleavable linkers are used in drug delivery, bioconjugation, and responsive materials.

Common motifs include disulfide bonds (R-S-S-R'), disulfide-containing crosslinks, and related structures such as selenenyl sulfide or diselenide linkages that respond to redox changes. The most widely used are disulfide bonds, which can be reduced by intracellular thiols to form two thiols, often releasing a bound payload. Some designs employ thioether or sulfoxide/sulfone motifs that undergo oxidation-reduction sequences to trigger cleavage or rearrangement.

Mechanism and design: In reducing environments, thiol-disulfide exchange or direct reduction converts disulfides into thiols, releasing the payload. Kinetics depend on bond strength, steric hindrance, and local redox potential, which varies by cell type and organelle. A major design consideration is chemical stability in blood versus rapid activation inside cells.

Applications include prodrug and antibody-drug conjugates, where a drug is linked to a targeting moiety by a redoxcleavable connector; redox-responsive polymers that release encapsulated cargo; and diagnostic probes whose signals change upon cleavage.

Challenges include premature or off-target cleavage, heterogeneity of redox environments, potential immunogenicity, and manufacturing complexity. Ongoing work seeks linkers with tunable sensitivity, improved biocompatibility, and expanded use in nanomedicine and materials science.