Hydrophobically Modified Paclitaxel Prodrug Enables Ultrahigh Drug Loading Driven by Polarity Redistribution

Controllable drug loading and self-assembly behaviors are vital to clinical applications of nanomedicines. Achieving high drug loading capacity (DLC) and stable self-assembly remains a significant challenge for hydrophobic chemotherapeutics such as paclitaxel (PTX). In this study, we propose a prodrug design strategy that significantly enhances loading efficiency. Unlike free PTX, which tends to aggregate uncontrollably, the designed prodrugs spontaneously self-assemble into uniform nanoparticles (100-200 nm) with an ultrahigh DLC exceeding 78 wt %. Molecular dynamics simulations reveal that hydrophobic modifications induce intramolecular polarity redistribution, with alkyl chains embedding within the nanoparticle core while polar moieties orient outward, stabilizing the assembled structures. The strategy is further validated by rational prodrug design and comprehensive in vitro and in vivo antitumor evaluations. Overall, the design principles established here offer a simple and versatile platform for optimizing nanomedicine formulations and advancing the clinical translation of high-DLC PTX prodrug nanomedicines.