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We report a mitochondria-targeted near-infrared probe (NRh-O) for frequency upconversion luminescence (FUCL) imaging of hypoxia. Under hypoxic conditions, NRh-O rapidly responds to release the FUCL product NRh (λex/em = 850/825 nm) with high sensitivity and selectivity in mitochondria. This highlights the potential application of a hypoxia-responsive probe in early clinical diagnosis. [ABSTRACT FROM AUTHOR]

Increasing interest has been noted in photosensitizer design. Currently, most small molecular photosensitizers have several drawbacks, including limited penetration depth and unsatisfying photostability. For addressing these limitations, Frequency upconversion luminescence (FUCL) small molecule was adopted as a photosensitizer design strategy for its deeper penetration, sensitive imaging, and better photostability. We developed a series of FUCL (NIR-NH 2 , NIR-NHEt, NIR-NEt 2) molecules with rigid structures. Equipped with the most powerful electron donor, NIR-NEt 2 exhibits the highest singlet oxygen generation, the strongest upconversion luminescence intensity under 808 nm irradiation and mitochondria-targeted ability. FUCL can be a superior molecular platform for image-guided photodynamic therapy of cancer cells. We developed a series of mitochondria-targeted small FUCL molecules (NIR-NH 2 , NIR-NHEt, and NIR-NEt 2) with different electron-donating segments and screened for the most outstanding one, NIR-NEt 2 , applied for the photodynamic therapy of cancer cells, which demonstrating a new molecular platform for deep-seated upconversion photodynamic therapy. [Display omitted] • FUCL is a one-photon process with advantages of deeper penetration, higher signal-to-noise ratio, and more excellent photostability over the traditional down-conversion luminescence. • NIR-NEt 2 was screened from a series of frequency upconversion luminescence molecules for the excellent photostability, best FUCL ability and ROS generation. • The tactic of heavy-atom free of FUCL PSs that modify strong donating groups on the electron-donating part of D-A structure was investigated. [ABSTRACT FROM AUTHOR]

[Display omitted] • NO chemically caged in rhodamine-containing frequency upconversion luminescence (FUCL) dyes. • NO prodrug PEG-Bn-NO exhibited excellent spatiotemporal uncaging controllability upon direct near-infrared light activation. • Immediate and precise exposure of cancer cell to NO was achieved for efficient gas therapy. • Highly sensitive FUCL readout offered deep-tissue tumor imaging while confirming accurate drug delivery. Gas therapy has emerged as an effective cancer treatment for minimal tissue invasiveness and little drug resistance. Particularly, Nitric oxide (NO) gas transmitter has drawn extensive attention for direct cancer-killing efficiency at high concentrations. However, the major drawbacks of the current NO prodrugs are insufficient NO delivery to the target tissues and lack the ability of spatiotemporal release precision. Meanwhile, it is also underestimated for NO prodrugs to achieve real-time deep-tissue drug monitoring visualization with high sensitivity for reliable delivery confirmation. Herein, two near infrared (NIR) light-triggered NO-releasing donors (NRh-Bn-NO and NRh-Et-NO) are synthesized for NO delivery with superb spatiotemporal controllability while tracing drug release mediated by frequency upconversion luminescence (FUCL) readout. FUCL is a unique anti-Stokes luminescence imaging modality that provides superior imaging sensitivity and increased signal-to-noise ratio for high resolution, which takes precedence in deep-seated tumor imaging. Furthermore, a nano-system (PEG-Bn-NO) is constructed with NRh-Bn-NO to guarantee efficient NO generation by direct NIR activation while allowing high-resolution drug monitoring in depth. Following intravenous administration, PEG-Bn-NO is specifically targeted to the tumor site and selectively controlled tumor growth induced by NIR light. The NO nano-prodrug should be inspirational to highly efficient gas therapy integrated with real-time drug delivery monitoring. [ABSTRACT FROM AUTHOR]