Engineering a hyaluronic acid-encapsulated tumor-targeted nanoplatform with sensitized chemotherapy and a photothermal effect for enhancing tumor therapy

Chemotherapy remains one of the most widely used cancer treatment modalities in clinical practice. However, the characteristic microenvironment of solid tumors severely limits the anticancer efficacy of chemotherapy. In addition, a single treatment modality or one death pathway reduces the antitumor outcome. Herein, tumor-targeting O 2 self-supplied nanomodules (CuS@DOX/CaO 2 -HA) are proposed that not only alleviate tumor microenvironmental hypoxia to promote the accumulation of chemotherapeutic drugs in tumors but also exert photothermal effects to boost drug release, penetration and combination therapy. CuS@DOX/CaO 2 -HA consists of copper sulfide (CuS)-loaded calcium peroxide (CaO 2 ) and doxorubicin (DOX), and its surface is further modified with HA . CuS@DOX/CaO 2 -HA underwent photothermal treatment to release DOX and CaO 2 . Hyperthermia accelerates drug penetration to enhance chemotherapeutic efficacy. The exposed CaO 2 reacts with water to produce Ca 2+ , H 2 O 2 and O 2 , which sensitizes cells to chemotherapy through mitochondrial damage caused by calcium overload and a reduction in drug efflux via the alleviation of hypoxia. Moreover, under near infrared (NIR) irradiation, CuS@DOX/CaO 2 -HA initiates a pyroptosis-like cell death process in addition to apoptosis. In vivo, CuS@DOX/CaO 2 -HA demonstrated high-performance antitumor effects. This study provides a new strategy for synergistic enhancement of chemotherapy in hypoxic tumor therapy via combination therapy and multiple death pathways.