Programmable Nanostructure Assembly of a Paclitaxel Derivative Enables Tunable Anticancer Therapy via Hydrogen Bond Engineering

Precise control of the morphology of self-assembling drugs is critical for optimizing their pharmacokinetics and therapeutic efficacy. However, adapting a single drug for diverse therapeutic applications by tailoring its structure remains a central challenge. Here, we report a hydrogen-bond-guided strategy to program the morphology of a paclitaxel derivative, PTP, by introducing a phosphate group to promote supramolecular organization. PTP molecules spontaneously formed nanofibers in aqueous environments via directional hydrogen bonding. Through rational coassembly with polyethylene glycol 400 or hyaluronic acid, the nanofibers were, respectively, transformed into spherical nanoparticles (PTP@PEG) or bundled fibers (PTP@HA), enabling tailored pharmacological performance. PTP@PEG enhanced systemic circulation, reduced renal accumulation, and improved antitumor efficacy in a murine 4T1 breast cancer model following intravenous administration. In contrast, PTP@HA exhibited sustained release and potent therapeutic effects in a peritoneal metastasis model of colorectal cancer via intraperitoneal injection. This work demonstrates how tunable hydrogen bonding enables precise programming of drug assembly morphology, offering a versatile platform to expand the therapeutic applications of a single drug across multiple diseases. Tuning the nanostructure of one drug using simple excipients via hydrogen bonds presents a simple and effective approach over designing new carriers, potentially revitalizing drugs previously limited by suboptimal pharmacokinetic or pharmacodynamic profiles.