Satellite-type Sulfur Atom Distribution in Trithiocarbonate Bond-Bridged Dimeric Prodrug Nanoassemblies: Achieving Both Stability and Activatability.

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 cell. 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. This article is protected by copyright. All rights reserved.