Suffering from the laborious synthesis and undesirable tumor microenvironment response,t he exploitation of novel NIR-II absorbing organic photothermal agents is of importance to promote phototherapeutic efficacy.Herein, two kinds of charge-transfer complex nanoparticles (TMB-F4TCNQ and TMB-TCNQ) are prepared by supramolecular assembly.Because of the larger energy gap between donor and acceptor,T MB-F4TCNQ presents higher charge-transfer degree (72 %) than that of TMB-TCNQ (48 %) in nanoaggregates.T herefore,T MB-F4TCNQ exhibits stronger NIR-II absorption ability with am ass extinction coefficient of 15.4 Lg À1 cm À1 at 1300 nm and excellent photothermal effect. Impressively,the specific cysteine response can make the TMB-F4TCNQ effectively inhibit the intracellular biosynthesis of GSH, leading to redoxd syhomeostasis and ROS-mediated ferroptosis.T MB-F4TCNQ can serve as ac ontrast agent for NIR-II photoacoustic imaging to guide precise and efficient photothermal therapyinv ivo.

HIGHLIGHTS • Self-oxygenation/degradable nanozyme reactors with core-shell structure were fabricated for relieving tumor hypoxia. • Intratumoral hypoxia alleviation and sensitization of immunochemotherapy using as-prepared nanozyme reactors was demonstrated in B16F10 melanoma tumor. ABSTRACT Recently emerged cancer immunochemotherapy has provided enormous new possibilities to replace traditional chemotherapy in fighting tumor. However, the treatment efficacy is hampered by tumor hypoxiainduced immunosuppression in tumor microenvironment (TME). Herein, we fabricated a self-oxygenation/degradable inorganic nanozyme with a core-shell structure to relieve tumor hypoxia in cancer immunochemotherapy. By integrating the biocompatible CaO 2 as the oxygen-storing component, this strategy is more effective than the earlier designed nanocarriers for delivering oxygen or H 2 O 2 , and thus provides remarkable oxygenation and long-term capability in relieving hypoxia throughout the tumor tissue. Consequently, in vivo tests validate that the delivery system can successfully relieve hypoxia and reverse the immunosuppressive TME to favor antitumor immune responses, leading to enhanced chemoimmunotherapy with cytotoxic T lymphocyte-associated antigen 4 blockade. Overall, a facile, robust and effective strategy is proposed to improve tumor oxygenation by using self-decomposable and biocompatible inorganic nanozyme reactor, which will not only provide an innovative pathway to relieve intratumoral hypoxia, but also present potential applications in other oxygen-favored cancer therapies or oxygen deficiency-originated diseases.

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Biocatalytic design of nanomaterials with enzyme-like activity has been considered as a reliable and promising toolkit for the generation of diagnostic agents in complex biological microenvironments. However, preparation of nanomaterials...

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