Currently, some approaches in cancer therapy have gradually shifted from a focus on monotherapy to combined therapy, which results in considerable superadditive therapeutic effects. Herein, bovine serum albumin integrated manganese dioxide nanoparticles (BSA-MnO 2 ) was synthesized via a biomineralization strategy. Then, the BSA-MnO 2 nanoparticles was anchored on the surface of the chemotherapeutic drug doxorubicin (DOX) and photosensitizer chlorine e6 (Ce6) co-loaded hollow mesoporous silica nanospheres (BSA-MnO 2 @HMSNs-DOX-Ce6, BMHDC) through the formation of disulfide bonds. The BSA-MnO 2 gatekeeper can not only prevent the premature release of payloads, but also act as an oxygen generator by triggering the decomposition of endogenous H 2 O 2 , which is able to overcome the hypoxia-associated photodynamic therapy (PDT) resistance of tumors. The high stability of the fabricated BMHDC nanoparticles with appropriate sizes (150 nm) could prolong blood circulation time and increase tumor accumulation compared to HMSNs-DOX-Ce6 nanoparticles. Notably, such nanoplatform exhibits efficient payloads loading capacities (14% for DOX and 36% for Ce6) and pH/redox-sensitive DOX and Ce6 release behavior through the breakage of disulfide bonds in the presence of the intracellular GSH, thus lead to synergistic chemo-PDT effect with a combination index (CI) of 0.21. In vitro and in vivo experiments confirmed that the flexible BMHDC nanoplatforms can effectively suppress human cervical carcinoma via synergistic therapy. The facile incorporation of the albumin-based gatekeeper into hollow mesoporous silica nanoparticle-based nanosystem has great potential for efficient stimuli-responsive drug delivery and other oxygen dependent therapy. © 2019 Elsevier B.V.