Dual Noncovalent Binding Modes Enabled via Single Thiourea Motif: An Emerging Arsenal for Supramolecular Polymeric Nanomedicine

Abstract

Abstract The structural rigidity of thiourea (TU) motifs has made them useful in supramolecular (bio)materials. However, the role of the TU motif in a single system endowing dual noncovalent interactions, i.e., Hydrogen‐bonding (H‐bonding) association and metal‐coordination interaction, to afford nanomedicine is still unexplored. Herein a smart supramolecular polymeric nanomedicine constructed via TU motifs privileged dual noncovalent interactions, toward synergistic chemo/chemodynamic (CT/CDT) cancer therapy is reported. The study first synthesized a six‐arm star‐shaped amphiphilic polymer vehicle containing pendant TU motifs, poly(acylthiourea‐ co ‐oligo(ethylene glycol) ethyl acrylate) 6 (P(TU‐ co ‐OEGEA) 6 ), followed by addressing both H‐bonding association and metal‐coordination to fabricate supramolecular nanomedicine (e.g., Dox/Cu@P(TU‐ co ‐OEGEA) 6 ). Structural privilege and functional diversity of TU motifs constitute an outstanding scaffold, not only offering an H‐bonding site to associate doxorubicin (Dox) but also acting as a ligand to coordinate copper (Cu). Thereby, one TU motif can enable dual noncovalent binding modes, triggering multiple curative outcomes. TU/Dox and TU/Cu noncovalent interactions can induce intermolecular configuration, yielding prompted cargo loading and in vivo stability. Moreover, benefiting from pH‐responsive Dox release and Fenton‐like copper redox chemistry, accompanied by Dox‐induced intratumoral H 2 O 2 elevation and prompted •OH generation, synergistic CT/CDT with extraordinary anti‐tumor efficacy is indeed accomplished. This work provides a new paradigm using TU motifs regulated dual supramolecular forces to meet therapeutic goals.