20 To overcome the tumor hypoxia and elevate PDT efficacy, five primary approaches have been instigated: (1) the exploration of oxygen carriers such as perfluorocarbon and hemoglobin for exogenous delivery of oxygen into tumors 21,22 (2) the design of smart nano-systems for the in situ generation of oxygen inside the solid tumor 23,24 (3) the development of a novel strategy to regulate tumor metabolism such as inhibiting tumor cellular respiration and the hypoxia-inducible factor-1 (HIF-1) signaling pathway to relive tumor hypoxia 25–27 (4) the synthesis of Type-I PSs with relatively O 2 independent properties for PDT 28–30 and (5) the combination of other therapy methods such as catalytic therapy, 31,32 PTT, 33 and chemotherapy 34,35 to enhance the therapeutic effect. 19 However, the hypoxia of the TME significantly limits the therapeutic efficacy of PDT while directly inducing the malignant progression of tumors. 18 In the process of PDT, photosensitizers (PSs) transfer light energy to the adjacent oxygen for the generation of ROS such as 1O 2 to kill cancer cells. Among these methods, PDT has evolved as a clinically approved anticancer strategy due to its minimal invasiveness and selective cytotoxic activity toward malignant cells. 5 On this basis, ROS-mediated therapeutic methods, such as photodynamic therapy (PDT), 6–11 catalytic therapy, 12–16 and sonodynamic therapy, 17 are developed to induce elevated oxidative stress and death of cancer cells by generating excess ROS.

4 This confers a state of increased basal oxidative stress to tumor cells, making them more sensitive to further augment ROS. 2,3 Elevated ROS levels is a characteristic of the tumor microenvironment (TME), and with the high ROS elimination rates in cancer cells this drives tumor progression. 1 However, abnormal ROS levels tend to damage biologically active molecules in cells, such as DNA, proteins and lipids, causing cellular impairment. Introduction As an essential participant of vital movement, reactive oxygen species (ROS), mainly consisting of hydroxyl radicals (˙OH), superoxide anions (O 2˙ −) and singlet oxygen ( 1O 2), play an important role in signal transduction and cell cycle progression. In this work, a novel nanoplatform for multiple ROS-mediated synergistic photodynamic/catalytic therapy of hypoxic tumors has been fabricated. Additionally, due to the interaction between HA and overexpressed receptors (cluster determinant 44) in cancer cells, HA-PCD exhibits tumor cell targetability. The loaded Pt NPs can not only enhance photodynamic therapy under hypoxic conditions by producing oxygen via catalase-mimicking activity, but also generate hydroxyl radicals (˙OH) and superoxide anions (O 2˙ −) for catalytic therapy because of its peroxidase- and oxidase-mimicking activities. Under 635 nm laser irradiation, HA-PCD generates singlet oxygen ( 1O 2) due to the involvement of CDs photosensitizers. Here, we report a triple ROS-generator, hyaluronic acid-modified Pt nanoparticles/carbon dots-loaded mesoporous silica (HA-PCD), which consists of Pt nanoparticles (NPs) and carbon dots (CDs)-loaded dendritic mesoporous silica nanoparticles (DMSNs) with further surface modifying hyaluronic acid (HA) for photodynamic/catalytic combination therapy of hypoxic tumors. The development of an effective nanoplatform based on PDT toward hypoxic tumors remains a research imperative. The therapeutic efficacy of reactive oxygen species (ROS)-mediated cancer treatments is significantly limited by a shortage of substrates, such as hypoxia in photodynamic therapy (PDT).

Silica sao