A smart O_(2)-generating nanocarrier optimizes drug transportation comprehensively for chemotherapy improving

Drug transportation is impeded by various barriers in the hypoxic solid tumor,resulting in compromised anticancer efficacy.Herein,a solid lipid monostearin(MS)-coated CaO_(2)/MnO_(2) nanocarrier was designed to optimize doxorubicin(DOX)transportation comprehensively for chemotherapy enhancement.The MS shell of nanoparticles could be destroyed selectively by highly-expressed lipase within cancer cells,exposing water-sensitive cores to release DOX and produce O_(2).After the cancer cell death,the core-exposed nanoparticles could be further liberated and continue to react with water in the tumor extracellular matrix(ECM)and thoroughly release O_(2) and DOX,which exhibited cytotoxicity to neighboring cells.Small DOX molecules could readily diffuse through ECM,in which the collagen deposition was decreased by O_(2)-mediated hypoxia-inducible factor-1 inhibition,leading to synergistically improved drug penetration.Concurrently,DOX-efflux-associated P-glycoprotein was also inhibited by O_(2),prolonging drug retention in cancer cells.Overall,the DOX transporting processes from nanoparticles to deep tumor cells including drug release,penetration,and retention were optimized comprehensively,which significantly boosted antitumor benefits.