Fibronectin-modified pH/ATP-responsive ZIF-90 nanoparticles induce ferroptosis in colorectal cancer via mitochondrial dysfunction

Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide, and conventional therapies are often limited by low efficacy and severe side effects. Emodin (EO), a natural anthraquinone compound, exhibits notable anticancer activity but is hindered by poor stability, low bioavailability, and potential toxicity. To overcome these limitations, we developed a pH/ATP-responsive nanoplatform by coordinating EO with Fe(Ⅲ) (EO–Fe), encapsulating the complex within Zeolitic Imidazolate Framework-90 nanoparticles (ZIF-90 NPs), and functionalizing the surface with fibronectin (FN) to obtain EO–Fe@ZIF-90–FN NPs. The nanocarrier exhibited favorable physicochemical properties, good biocompatibility, and controlled release of EO and Fe under acidic and ATP-rich conditions that mimic the tumor microenvironment. In vitro, EO–Fe@ZIF-90–FN NPs significantly inhibited the proliferation and migration of SW480 and HCT-116 cells and promoted apoptosis. Mechanistic studies revealed that EO–Fe@ZIF-90–FN NPs induced ferroptosis by regulating mitochondrial dysfunction. In vivo, EO–Fe@ZIF-90–FN markedly suppressed tumor growth in CRC xenograft models. These findings demonstrate that EO–Fe@ZIF-90–FN NPs exert potent antitumor activity by inducing ferroptosis and mitochondrial dysfunction, providing a promising nanotherapeutic strategy for CRC treatment.