Molecularly Tailored Artesunate Nanomedicine with Well-Balanced Nanoassembly and Anticancer Performance

<b>Background</b>: Artesunate (ART), a natural product derivative of artemisinin, exhibits striking antitumor activity. However, the clinical translation of ART is limited by rapid clearance, poor tumor selectivity, and severe off-target toxicity. To address these limitations, we developed an unsaturated aliphatic chain-driven nanoassembly strategy to optimize the therapeutic performance of ART. <b>Methods</b>: We designed and synthesized two ART derivatives by conjugating saturated aliphatic chains (ART-SAs) or unsaturated aliphatic chains (ART-LAs) to ART, which subsequently self-assembled into carrier-free nanoassemblies (NAs). These NAs were characterized for their self-assembly capacity and colloidal stability. Biological evaluations included studies on cellular uptake efficiency, in vivo pharmacokinetics, and antitumor efficacy in a tumor-bearing mouse model. <b>Results</b>: The saturated aliphatic chain is found to drive nanoassembly of ART-SA but significantly shields the antitumor activity of ART. Interestingly, the conjugate of an unsaturated aliphatic chain to ART (ART-LA) not only shows outstanding self-assembly capacities but also retains the native antitumor activity of ART. The P-AL NAs with improved pharmacokinetics and tumor-specific biodistribution exert potent antitumor activity and favorable safety. <b>Conclusions</b>: We successfully applied ART for highly effective antitumor therapy by employing an unsaturated aliphatic chain-driven strategy. This study is conducive to promoting the clinical application of ART.