Self-assembly and self-delivery of the pure nanodrug dihydroartemisinin for tumor therapy and mechanism analysis

Dihydroartemisinin (DHA), a plant-derived natural product, has recently been proven to be an effective therapeutic agent for cancer treatment. Nevertheless, the poor water solubility and low bioavailability of DHA seriously impede its clinical applications. Herein, a simple and green strategy based on the self-assembly of DHA was developed to synthesize carrier-free nanoparticles (NPs). The resulting nanodrug (DHA NPs) was formed by the self-assembly of DHA molecules via hydrogen bonding and hydrophobic interactions. The DHA NPs exhibited a near-spherical morphology with narrow size distribution, favorable drug encapsulation efficiency (>92%), excellent stability, and on-demand drug release behavior. Furthermore, the in vitro and in vivo experiments revealed that the DHA NPs exhibited significantly higher therapeutic efficacy than the DHA equivalent. In addition, we further explored the potential molecular mechanism of the DHA NPs by utilizing RNA-seq technology and western blotting analysis, which demonstrated that the p53 signaling pathway plays a crucial part in the process of inhibiting tumor cell growth and inducing apoptosis. This work not only reveals the rationale for developing pure nanodrugs via the self-assembly of natural small molecules for oncotherapy but also the investigation of the antitumor mechanism and provides novel theoretical support for the clinical usage of DHA.