ROS‐Responsive Thioketal–Mesoporous Silica Nanoparticles Codelivering Saikosaponin D Suppress Colorectal Cancer Liver Metastasis by Boosting Antitumor Immunity

Background Colorectal cancer (CRC) often metastasizes to the liver, which complicates treatment strategies. This study evaluates MSN–TK@SA, a mesoporous silica nanoparticle (MSN) loaded with saikosaponin D (SA) and reactive oxygen species (ROS)–cleaving thioketal (TK), as a targeted approach for CRC metastasis. Methods MSN–TK@SA nanoparticles were formulated by loading SA onto MSN to create MSN@SA, followed by coating with ROS‐responsive methoxy polyethylene glycol‐thioketal‐N‐hydroxysuccinimide (mPEG‐TK‐NHS) to produce MSN–TK@SA. The nanoparticles were characterized using different analytical techniques, and drug release profiles were evaluated. CRC cells and a liver metastasis model of CRC with liver qi stagnation were treated with the nanoparticles, and various techniques were used to assess the effects of MSN–TK@SA on tumorigenicity, immune response, and liver metastasis. Results The MSN, MSN@SA, and MSN–TK@SA nanoparticles were spherical, monodispersed, and colloidally stable, with a progressive decrease in zeta potential, which demonstrated successful loading with SA and thioketal coating. Fourier‐transform infrared spectroscopy (FTIR) confirmed the silanol, amine, and PEG‐TK functionalization. MSN–TK@SA had high encapsulation (81%) and loading efficiency (29%), which was consistent with pore entrapment stabilized by hydrogen bonding and dipole interactions. Drug release was based on a sustained/controlled profile, and approximately 80% of the drug was released within 72 h without a burst effect. First‐order and Weibull models best described the concentration‐dependent, diffusion‐controlled release with anomalous transport of the nanoparticles. In vitro, MSN–TK@SA exhibited significant anticancer activity, including decreased viability, invasion, and migration, and amplified apoptosis of CRC cells. MSN–TK@SA markedly reduced tumor burden and metastasis, enhanced antitumor immunity, and inhibited inflammation in a CRC liver metastasis model. Conclusion MSN–TK@SA nanoparticles enable effective drug loading, controlled release, and immune activation, significantly inhibiting CRC liver metastasis. They are a promising platform for drug delivery and immunotherapy, deserving further preclinical and translational research.