Disulfide-Functionalized Covalent Organic Frameworks as Nanocarriers Realizing Programmed Cellular Internalization and Drug Release

Covalent organic frameworks (COFs) have shown great potential in bioactive molecule delivery, but their pharmaceutical effects are often hindered by their limited cell-penetrating ability and uncontrolled drug release. In this study, we integrated redox-responsive disulfide motifs into COF backbones and prepared glutathione-sensitive SS_<i>x</i>-COFs with tunable disulfide densities. These nanocarriers featured high specific surface areas and exceptional drug loading capacities. Notably, the incorporation of disulfide significantly enhanced the cellular uptake of COFs and accelerated their drug release kinetics, both of which can be regulated by the stoichiometric control of disulfide contents within COF structures. Mechanistic investigations revealed that the cellular uptake enhancement was attributed to a thiol-disulfide exchange-mediated internalization pathway. In vitro and in vivo studies showed that the drug-loaded nanocarriers, especially SS₇₀-COF_Dox, exhibited excellent antitumor efficacy. This work highlights the potential to regulate the intracellular delivery efficiency of nanocarriers by surface disulfide engineering, offering valuable insights for designing efficient stimuli-responsive drug delivery systems.