Multiple-Responsive Mesoporous Silica Nanoparticles for Highly Accurate Drugs Delivery to Tumor Cells

[Image: see text] A core–shell nanocarrier with triple layers, where each layer is sensitive to one specific physiological stimulus, has been fabricated for highly accurate cancer therapy. The nanocarrier consists of mesoporous silica nanoparticles (core structure for drug loading), fluorescein isothiocyanate-labeled hyaluronan (FITC–HA, first shell for imaging with enzymatic response), disulfide bond-embedded silica (SiO(2), second layer with glutathione response), and switchable zwitterionic surface (third layer with pH response). The nanocarrier decorated with zwitterionic surface is able to offer long blood circulation time due to the weak nonspecific protein absorption. After these nanocarriers were gradually gathered around tumor cells through enhanced permeability and retention effect, the zwitterionic surface could switch to positive charge in low-pH environment, which was in favor of cellular uptake due to the strengthened positive nanocarrier–negative cellular membrane interaction. Once internalized into tumor cells, the high concentration of glutathione in cytoplasm could cleave disulfide bonds to remove the SiO(2) shell and the HA layer would be exposed, which would be further degraded by hyaluronidase to trigger payload release. The fluorescent spectrum and images reveal that both glutathione and hyaluronidase are required for the release of preloaded drugs from these nanocarriers. By employing the multiple response, our nanocarriers could achieve effective antibiofouling ability while maintaining enhanced cellular internalization and targeted drug delivery, resulting in preferred cancer cell cytotoxicity, which is much higher than that of free doxorubicin. The in vitro data exhibited that our nanocarriers may provide an effective strategy for accurate cancer treatment.