Hypoxia has been firmly correlated to the drug resistance of solid
tumors. Alleviation of
hypoxia by
tumor reoxygenation is expected to sensitize the
chemotherapy toward solid
tumors. Alternatively, ferroptosis provides a therapeutic strategy to overcome apoptotic resistance and multidrug resistance of solid
tumors, collaboratively strengthening the
chemotherapy toward hypoxic
tumors. Herein, an ultrasound (US)-activatable nanomedicine was developed for overcoming
hypoxia-induced resistance to
chemotherapy and efficiently inhibiting
tumor growth by inducing sensitized apoptosis and collaborative ferroptosis of
tumor cells. This nanomedicine was constructed by integrating
ferrate and
doxorubicin into biocompatible hollow mesoporous
silica nanoplatforms, followed by assembling a solid-liquid phase-change material of
n-heneicosane. The US-induced mild
hyperthermia initiates the phase change of
n-heneicosane, enabling US-activated co-release of
ferrate and
doxorubicin. Results reveal that the released
ferrate effectively reacts with water as well as the over-expressed
hydrogen peroxide and
glutathione in
tumor cells, achieving tumor-microenvironment-independent reoxygenation and
glutathione-depletion in
tumors. The reoxygenation down-regulates expressions of
hypoxia-inducible factor 1α and multidrug resistance gene/transporter
P-glycoprotein in
tumor cells, sensitizing the apoptosis-based
doxorubicin chemotherapy. More importantly, exogenous
iron metabolism from the nanomedicine initiates intracellular Fenton reactions, leading to
reactive oxygen species overproduction and
iron-dependent ferroptotic death of
tumor cells. Furthermore, the
glutathione-depletion inactivates the
glutathione peroxidase 4 (GPX4, a critical regulatory target in ferroptosis), inhibiting the reduction of
lipid peroxides and reinforcing the ferroptotic cell death. The sensitized
chemotherapy together with the
iron-dependent ferroptosis of
tumor cells play a synergistic role in boosting the growth suppression of hypoxic
osteosarcoma in vivo. Additionally, the nanomedicine acts as a nanoprobe for in vivo photoacoustic imaging and
glutathione tracking, showing great potential as
theranostic agents for hypoxic solid
tumors treatment.