Structural Topology of Prodrug Nanoassembly: First Steps Toward Nano‐QSAR

ABSTRACT Small‐molecule prodrug nanoassemblies (SMP‐NAs) represent a promising nanomedicine for cancer therapy, enabling carrier‐free characteristics and facile fabrication. However, the development of SMP‐NAs currently relies on empirical trial‐and‐error screening, as quantitative descriptors to predict the relationship between molecular structure and self‐assembly remain unavailable. Here, we introduce chemical topology indices, traditionally restricted to small‐molecule drug discovery, as predictive tools for the rational design of SMP‐NAs. We synthesized three topological SN38 prodrugs with distinct topological architectures (linear, cyclic and branched) but identical lipophilicity. Topological indices quantitatively capture the critical molecular characteristics of the prodrugs. Notably, the branched architecture (SN38‐Br) provides molecular flexibility for efficient core packing while maintaining sufficient steric hindrance to prevent over‐aggregation. Consequently, SN38‐Br NPs exhibited superior colloidal stability, systemic blood circulation, robust tumor accumulation and antitumor activity. Our work establishes a theoretical framework for the quantitative structure‐activity relationship (QSAR) of SMP‐NAs, offering a blueprint for the transition from empirical screening to Nano‐QSAR.