and depletable H 2 O 2 [7] in TME also lead the cellular ROS level greatly diminished. Therefore, TME regulations especially regulating the content of O 2 , H 2 O 2 and GSH, are beneficial to most ROS production and of great significance for the ROS-mediated antitumor therapies.In recent years, there are plenty researches about how to deal with the hypoxia problem, which can mainly be divided into two modes, using carriers to deliver O 2 [8] or catalyzing the decomposition of endogenous H 2 O 2 . [9] While oxygen delivery would be compromised by gas leakage during storage and blood circulation. Compared with the former, the second mode of oxygen production is more stable and specific, whereas the limited level (<100 µM) of H 2 O 2 cannot support the enough O 2 . On the other hand, glucose-oxidase (GOx) [10] and Au [11] etc. are often used to catalyze the oxidation of glucose to H 2 O 2 for further production of ROS, but this H 2 O 2 generation process relies on oxygen and is limited by hypoxia. Hence, directly O 2 /H 2 O 2 self-supplied nanoagents are urgently needed. In view of this, one kind of metal peroxides (such as calcium peroxide, [12] magnesium peroxide, [13] zinc peroxide, [14] copper peroxide (CuO 2 ) [15] etc.) that can be decomposed into O 2 , H 2 O 2 , and M n+ in responsive to acidic TME, have attracted much attention in the antitumor fields. Among the above metallic element, Cuprum is the most popular one that performs well in the medical and biological fields, especially antitumor field. [16] More importantly, Cu 2+ possesses the capability to oxidize GSH into GSSG, thus reducing GSH level in cancer cells. Therefore, it is worth considering that combining oxygen-depended photosensitizer with CuO 2 may have great significance for the development of future ROS-mediated antitumor system.Herein, indocyanine green (ICG) was used as the photosensitizer to explore the influence of CuO 2 on PDT. And in order to combine the above components, the disulfide-bond-incorporated dendritic mesoporous organosilica (DMOS) was applied as a nanocarrier, thus forming the DMOS@CuO 2 @ICG-HA (DCI) nanocomposites (NCs), as shown in Scheme 1. After accumulating at the tumor sites, the CuO 2 of DCI NCs could be decomposed into O 2 , H 2 O 2 , and Cu 2+ in the acidic TME, resulting in hypoxia alleviation of tumor sites and enhanced PDT effect. Besides, the additional H 2 O 2 can ensure the effect of Cu 2+ mediated CDT efficacy. More importantly, Cu 2+ and Hypoxia, overexpressed glutathione (GSH) and depletable H 2 O 2 in tumor microenvironment (TME) are three major obstacles to the development of reactive oxygen species (ROS)-mediated antitumor therapy. Herein, a photodynamic/chemodynamic synergistic therapeutic nanoagent, DMOS@CuO 2 / ICG-HA (DCI), is synthesized based on copper peroxide (CuO 2 ) and indocyanine green (ICG) co-loaded disulfide-bond-incorporated dendritic mesoporous organosilica (DMOS), with modification of hyaluronic acid (HA). The DCI nanocomposites (NCs) can realize multiple TME regulating ability t...
