Self-assembled phenylboronic acid nanomedicine targets sialic acid to synergistically activate ferroptosis via RRM1 suppression and GPX4 Inhibition for precision colon cancer therapy.

Despite the promise of ferroptosis in cancer therapy, its insufficient potency and off-target toxicity remain significant challenges. Few studies have explored the therapeutic potential of nanoparticle (NP)-mediated active targeting strategies to induce robust ferroptosis in colon cancer (COC) cells effectively. In this study, we developed sialic acid (SA)-targeted NPs by conjugating artesunate (ART) with alanine (Ala) and phenylboronic acid (PBA) to formulate ART-Ala-PBA NPs (AAP NPs). Compared with nontargeted ART-Ala NPs, AAP NPs accumulated significantly within cancer tissues, inhibited tumor growth, and improved the survival rates of mice with COC, while exhibiting minimal toxicity. Mechanistically, AAP NPs induce ferroptosis through the accumulation of reactive oxygen species and the downregulation of the SLC7A11-GPX4 axis. Deep data-independent acquisition (DIA) proteomics revealed a novel suppression of ribonucleotide reductase regulatory subunit M1 (RRM1), which synergizes with canonical ferroptosis pathways to amplify lipid peroxidation. RNA sequencing further indicated that AAP NPs uniquely modulate autophagy-related processes, suggesting a multimodal mechanism distinct from the alterations in amino acid metabolism induced by parental ART formulations. Collectively, AAP NPs represent the first carrier-free nanoassembly leveraging PBA-mediated SA targeting to co-activate ferroptosis via dual ROS/GPX4-RRM1 regulation, offering a translatable paradigm for precision nanotherapy of COC.