Enzyme-powered nanomotors with enhanced cell uptake and lysosomal escape for combined therapy of cancer

Abstract

Low cellular uptake and lysosomal degradation are key difficulties of drug delivery in cancer treatment. Here, we report a novel nanomotor which can accomplish self-propulsion under the tumoral endogenous hydrogen peroxide to achieve high cell uptake rate and lysosomal escape. Calcium carbonate nanoparticles were employed as the core with polyethyleneimine (PEI) and catalase (CAT) acting as the shell to prepare the nanomotor via layer-by-layer self-assembly technology. To achieve local administration and slow release inside tumor, the nanomotors were loaded in Schiff-base hydrogel to build NM@hydrogel system. Taking advantage of the tumor microenvironment featured with an acidic pH and a high amount of hydrogen peroxide, the nanomotors were released from NM@hydrogel system in response to weak acidic tumor matrix. The released nanomotors can be autonomously propelled by the oxygen gradient generated from catalytic decomposition of hydrogen peroxide with a speed at 10.1±1.1 µm/s in 0.1 mM H2O2. Furtherly, combined with autonomous motion of nanomotors, specific tumor affinity strategy mediated by folic acid (FA) modification on the nanomotors was also proposed in the NM@hydrogel system, which the cell uptake rate was enhanced to about 80.6±2.0%. Furthermore, after internalization, the nanomotors could also efficiently escape from lysosomes owing to the proton sponge effect caused by PEI, CO2 produced by the degradation of CaCO3 nanoparticles and autonomous motion, which facilitated PTX and siRNA to reach their intracellular target, tubulin. PTX and siRNA strongly affected properties of tubulin and resulted in tumor cell apoptosis. In vitro and in vivo studies demonstrated excellent antitumor effect of the NM@hydrogel. Therefore, we anticipate that the proposed system would provide new insight in the drug delivery for cancer treatment.