Morphology-Tunable Nanoparticles of Aspartic Acid Paclitaxel Conjugates for Breast Cancer Treatment

Abstract The structural morphologies of nanomaterials serve as vital determinants in their biological interactions and efficacy in vivo. Achieving programmable control over the assembly morphology solely through molecular design remains challenging. Herein, a supramolecular strategy to control the assembly morphology of prodrugs for the orchestration of drug delivery in vivo is reported. A paclitaxel prodrug (PCA) was synthesized by conjugating aspartic acid with paclitaxel through a succinyl linker. PCA can spontaneously self-assemble into nanofibers. Incorporating the diacylphosphatidylethanolamine-PEG2k (DSPE-PEG2k) induces a morphological transition from fibers to rods and ultimately to spheres. Molecular dynamics simulations show that intermolecular hydrogen bonds fall from approximately 50 in DP1 NFs to fewer than 5 in DP3 NPs, and carboxyl-related atoms in aspartic acid account for 53.24% of the total hydrogen bonds, proving that the carboxyl-mediated hydrogen-bond network dominates anisotropic assembly. Although fibrous and spherical assemblies exhibit the fastest release rate and optimized cellular delivery of paclitaxel in vitro, respectively, the rod-shaped assemblies achieve an optimal combination of prolonged blood circulation, enhanced tumor accumulation, and facilitated cellular internalization, resulting in superior antitumor efficacy in vivo, compared to fibrous and spherical counterparts and Abraxane. This study elucidates how supramolecular interactions regulate the macroscopic morphology of prodrug assemblies at the molecular level, establishing a design paradigm for engineering anisotropic nanomedicines with tailored in vivo fate.