Chalcogen-centered cascade exchange chemistry is increasingly understood to account for thiol-mediated uptake, that is, the ability of reversibly thiol-reactive agents to penetrate cells. Here, reversible Michael acceptors are shown to enable and inhibit thiolmediated uptake, including the cytosolic delivery of proteins. Dynamic cyano-cinnamate dimers rival the best chalcogen-centered inhibitors. Patterns generated in inhibition heatmaps reveal contributions from halogen-bonding switches that occur independent from the thyroid transporter MCT8. The uniqueness of these patterns supports that the entry of tetrel-centered exchangers into cells differs from chalcogen-centered systems. These results expand the chemical space of thiol-mediated uptake and support the existence of a universal exchange network to bring matter into cells, abiding to be decoded for drug delivery and drug discovery in the broadest sense.

Chalcogen‐centered cascade exchange chemistry is increasingly understood to account for thiol‐mediated uptake, that is, the ability of reversibly thiol‐reactive agents to penetrate cells. Here, reversible Michael acceptors are shown to enable and inhibit thiol‐mediated uptake, including the cytosolic delivery of proteins. Dynamic cyano‐cinnamate dimers rival the best chalcogen‐centered inhibitors. Patterns generated in inhibition heatmaps reveal contributions from halogen‐bonding switches that occur independent from the thyroid transporter MCT8. The uniqueness of these patterns supports that the entry of tetrel‐centered exchangers into cells differs from chalcogen‐centered systems. These results expand the chemical space of thiol‐mediated uptake and support the existence of a universal exchange network to bring matter into cells, abiding to be decoded for drug delivery and drug discovery in the broadest sense.

Naphthalenediimides (NDIs) are privileged scaffolds par excellence, of use in functional systems from catalysts to ion channels, photosystems, sensors, ordered matter in all forms, tubes, knots, stacks, sheets, vesicles, and colored over the full visible range. Despite this extensively explored chemical space, there is still room to discover core‐substituted NDIs with fundamentally new properties: NDIs with cyclic trisulfides (i.e., trisulfanes) in their core absorb at 668 nm, emit at 801 nm, and contract into disulfides (i.e., dithietes) upon irradiation at <475 nm. Intramolecular 1,5‐chalcogen bonds account for record redshifts with trisulfides, ring‐tension mediated chalcogen‐bond‐mediated cleavage for blueshifts to 492 nm upon ring contraction. Cyclic oligochalcogenides (COCs) in the NDI core open faster than strained dithiolanes as in asparagusic acid and are much better retained on thiol exchange affinity columns. This makes COC‐NDIs attractive not only within the existing multifunctionality, particularly artificial photosystems, but also for thiol‐mediated cellular uptake.

The colorful chemistry in the core of naphthalenediimides, aka NDIs, is represented by the Warholesque cover image, here with green, (infra)red‐fluorescent cyclic trisulfides, members of cell‐penetrating cyclic oligochalcogenides, and their photoinduced contraction into yellow cyclic disulfides. Absorption shifts by more than 170 nm because the through‐space distance between O and S increases by as little as 0.4 Å. More information can be found in the Communication by E. Vauthey, S. Matile, et al. on page 14059.