Cap-free dual stimuli-responsive biodegradable nanocarrier for controlled drug release and chemo-photothermal therapy

Construction of biocompatible functional nanocarrier for combination of chemo-photothermal therapy against cancer is cumulatively desirable, but still challenging, particularly in biodegradability and cap-free release fields. Herein, we synthesized a drug delivery system with cap-free and pH/redox-responsive properties by coating disulfide-bridged silica shell on CuS nanoparticles and simultaneously introducing hydrophobic nanochannels to seal doxorubicin (abbreviated as DMDBCP). The hydrophobic phenylamine-functionalized nanochannels on silica shell protected doxorubicin from being wetted by neutral solution in the transport process and released sealed doxorubicin after being protonated in acidic environment of cancer cells. Meanwhile, under the stimulation of plentiful glutathione in A549 cells, the disulfide-bridged structure was biodegradable, efficiently increasing the intracellular accumulation of doxorubicin to generate high cytotoxicity and shorten the retention time of nanocarriers. Furthermore, as a prominent photothermal therapy agent, CuS converted the near-infrared (NIR) optical energy to hyperthermia to ablate cancer cells and help doxorubicin release. Differing from the physical-blockage controlled release system, our cap-free system skillfully bypassed the capping units to achieve the pH/glutathione dual-responsive drug release, minimizing the adverse effects in transit. More importantly, this system achieved excellent therapeutic effect through the combination of chemo-photothermal therapy, and showed promising potential in clinical translation in the treatment of cancer.