Stepwise Unfolding of Single-Chain Nanoparticles by Chemically Triggered Gates

The orthogonal, stepwise, and order‐independent unfolding of single‐chain nanoparticles (SCNPs) is introduced as a key step towards actively controlling the folding dynamics of SCNPs. The SCNPs are compacted by multiple hydrogen bonds and host–guest interactions. Well‐defined diblock (AB) and tetrablock (ABCD) copolymers are equipped with orthogonal recognition motifs via modular ligation along the lateral chain. Initially, single‐chain folding of the diblock copolymer was induced by the host–guest complexation of benzo‐21‐crown‐7 (B21C7, host) and a secondary ammonium salt (AS, guest), representing an efficient avenue for single‐chain collapse. Next, both orthogonal Hamilton wedge (HW) and cyanuric acid (CA) as well as B21C7–AS motifs were employed to generate SCNPs based on the ABCD polymer system. Subsequently, the stepwise dual‐gated and order‐independent unfolding of the SCNPs was investigated by the addition of external stimuli. The folding and unfolding were explored by 1D 1H NMR spectroscopy, dynamic light scattering (DLS), and diffusion‐ordered NMR spectroscopy (DOSY). One step at a time: A single‐chain nanoparticle based on a well‐defined high‐molecular‐weight tetrablock copolymer equipped with mutually orthogonal folding elements undergoes order‐independent and highly orthogonal unfolding in response to simple chemical triggers.