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As a standard cancer treatment method, radiotherapy (RT) has cured or alleviated over half cancer bearing patients worldwide more than 100 years. However, the therapeutic outcome is seriously hindered by the resistant tumor microenvironment (TME). Hypoxia is a critical factor of vicious TME that causes radiation resistance owing to the insufficiency of oxygen for DNA damage maintenance. Moreover, severe vascular dysfunction and pyknomorphic extracellular matrix (ECM) in deep tumor tissues substantially limit radiosensitizer penetration and oxygen diffusion from vessels into tightly packed tumor core. In this study, we develop a hybrid transcytosis nanopomegranate (HTP) with high transcytosis potential in response to TME condition. HTP is architected by self-assembly of small CuS and Au nanoparticles (NPs) at normal physiological condition. HTP can rapidly collapse to transcytosis NPs (CuS and Au NPs) in TME with cationized surface, which enables excellent transcytosis potential and effectively elevates the penetration of CuS and Au into deep tumor tissues. Following the second near-infrared (NIR(II)) biowindow laser irradiation, CuS heats the tumor and enhances blood perfusion, eliciting tumor hypoxia alleviation and DNA damage aggravation. Moreover, Au NPs enriched in deep tumor tissues effectively sensitize radio-therapeutic response. Our study provides a new and potential nano-platform to ameliorate tumor hypoxia and sensitize deep tumor tissue radiotherapy.
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