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 (SiO2, 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 SiO2 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.