A Topology-to-Therapy Map for Prodrug Nanoassemblies

Self-assembled prodrug nanoassemblies integrate drug, response, and modification modules. Incorporating modification modules offers a strategy to balance efficacy-toxicity in cancer nanomedicine, yet how topology governs their structure-function relationship remains elusive. Here, we report a topological prodrug nanoassembly platform by conjugating docetaxel with fatty acid-based modification modules with linear, branched, or cyclic structure. This platform provides the systematic evidence that (i) topology dictates assembly mechanisms by modulating hydrophobic interactions and local energetic environments, as revealed through quantum chemical and multiscale analyses; and (ii) topology regulates bioactivity and toxicity in vitro/vivo, revealing a clear relationship of efficacy and safety. Nanoassemblies with linear modules excelled in key functional metrics, including assembly kinetics, release, and antitumor efficacy. Cyclic nanoassemblies maximized safety despite reduced potency, and branched nanoassemblies showed intermediate performance. By encoding performance into molecular topology, this work advances a key design parameter for prodrug-based cancer nanotherapeutics.