Drug transportation is impeded by various barriers in the hypoxic solid tumor,resulting in compromised anticancer efficacy.Herein,a solid lipid monostearin(MS)-coated CaO2/MnO2 nanocarrier was designed to optimize doxorubicin(DOX)transportation comprehensively for chemotherapy enhance-ment.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 O2.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 O2 and DOX,which exhibited cytotoxicity to neigh-boring cells.Small DOX molecules could readily diffuse through ECM,in which the collagen deposition was decreased by O2-mediated hypoxia-inducible factor-1 inhibition,leading to synergistically improved drug penetration.Concurrently,DOX-efflux-associated P-glycoprotein was also inhibited by O2,prolong-ing 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.