Satellite‐Type Sulfur Atom Distribution in Trithiocarbonate Bond‐Bridged Dimeric Prodrug Nanoassemblies: Achieving Both Stability and Activatability

Abstract Homodimeric prodrug nanoassemblies (HDPNs) hold promise for improving the delivery efficiency of chemo‐drugs. However, the key challenge lies in designing rational chemical linkers that can simultaneously ensure the chemical stability, self‐assembly stability, and site‐specific activation of prodrugs. The “in series” increase in sulfur atoms, such as trisulfide bond, can improve the assembly stability of HDPNs to a certain extent, but limits the chemical stability of prodrugs. Herein, trithiocarbonate bond (─SC(S)S─), with a stable “satellite‐type” distribution of sulfur atoms, is developed via the insertion of a central carbon atom in trisulfide bonds. ─SC(S)S─ bond effectively addresses the existing predicament of HDPNs by improving the chemical and self‐assembly stability of homodimeric prodrugs while maintaining the on‐demand bioactivation. Furthermore, ─SC(S)S─ bond inhibits antioxidant defense system, leading to up‐regulation of the cellular ROS and apoptosis of tumor cells. These improvements of ─SC(S)S─ bond endow the HDPNs with in vivo longevity and tumor specificity, ultimately enhancing the therapeutic outcomes. ─SC(S)S─ bond is, therefore, promising for overcoming the bottleneck of HDPNs for efficient oncological therapy.