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Hypoxia is a critical factor for restricting photodynamic therapy (PDT) of tumor, and it becomes increasingly severe with increasing tissue depth. Thus, the relief of deep tumor hypoxia is extremely important to improve the PDT efficacy. Herein, tumor microenvironment (TME)‐responsive size‐switchable hyaluronic acid‐hybridized Ru nanoaggregates (HA@Ru NAs) were developed via screening reaction temperature to alleviate deep tumor hypoxia for improving the tumor‐specific PDT by the artful integration multiple bioactivated chemical reactions in situ and receptor‐mediated targeting (RMT). In this nanosystem, Ru NPs not only enabled HA@Ru NAs to have near infrared (NIR)‐mediated photothermal/photodynamic functions, but also could catalyze endogenous H2O2 to produce O2in situ. More importantly, hyaluronidase (HAase) overexpressed in the TME could trigger disassembly of HA@Ru NAs via the hydrolysis of HA, offering the smart size switch capability from 60 to 15 nm for enhancing tumor penetration. Moreover, the RMT characteristics of HA ensured that HA@Ru NAs could specially enter CD44‐overexpressed tumor cells, enhancing tumor‐specific precision of phototherapy. Taken together these distinguishing characteristics, smart HA@Ru NAs successfully realized the relief of deep tumor hypoxia to improve the tumor‐specific PDT. [ABSTRACT FROM AUTHOR]

Treatment in combination with real-time monitoring of dynamic organelle changes is of great significance for evaluating therapeutic efficacy. However, it remains highly challenging to realize such specific treatment and monitoring in organelles. Herein, we developed one kind of red emissive two-photon carbon dots (TP-CDs) via an N doping strategy for nucleolus-targeted treatment combined with real-time monitoring of dynamic changes in the nucleolus. In the TP-CD system, N doping endows TP-CDs with intrinsic two-photon excitation, red emission at 605 nm, and singlet oxygen (1O 2) production under 638 nm laser irradiation. More importantly, N heterocycles induced by doping offers significant affinity for TP-CDs toward RNA to realize specific self-targeting toward nucleolus and fluorescence variation during the photodynamic therapy (PDT) via the cleaving of RNA chain by 1O 2 to dissociate TP-CDs@RNA complex. By combining 1O 2 production, fluorescent variation during the PDT process, long-wavelength excitation and emission characteristics, as well as specific self-targetability of nucleolus, TP-CDs can be considered as a kind of "smart" CDs to realize treatment in combination of real-time dynamic changes in nucleolus for the first time. [Display omitted] [ABSTRACT FROM AUTHOR]