Tumor oxygen spatial heterogeneity is a critical challenge for the photodynamic inhibition of solid tumors. Development of an intelligent nanoagent to initiate optimal therapeutics according to the localized oxygen levels is an effective settlement. Herein, we report an activatable nanoagent (BDP-Oxide nanoparticles (NPs)) to enable the oxygen auto-adaptive photodynamic/photothermal complementary treatment. Upon the nanoagent accumulated in the tumor region, the low extracellular pH could trigger the disassociation of the nanoagent to release the phototheranostic agent, BDP-Oxide, which will subsequently afford the fluorescence imaging-guided photodynamic oxidation after it gets into the outer oxygen-rich tumors. Along with the penetration deepening in the solid tumor, furthermore, BDP-Oxide could be reduced into BDP by the cytochrome P450 (CYP450) enzymes activated in the low oxygen tension regions of inner hypoxic tumors, which will switch on the photothermal and photoacoustic effects. Overall, the BDP-Oxide NPs-enabled photodynamic/photothermal complementary therapy significantly suppressed the solid tumor growth (inhibition rate of 94.8%). This work proposes an intelligent platform to address the oxygen partial pressure for the optimization of cancer phototherapeutics.

Controllably and efficaciously localized CRISPR/Cas9 plasmids transfection plays an essential role in genetic editing associated with various key human diseases. We employed near-infrared (NIR) light-responsive CRISPR/Cas9 plasmids delivery via a charge-reversal nanovector to achieve highly efficient and site-specific gene editing. The nanovector with abundant positive charges was fabricated on the basis of an ultraviolet-sensitive conjugated polyelectrolyte coated on an upconversion nanomaterial (UCNP-UVP-P), which can convert into negative charges upon 980 nm light irradiation. Using the as-prepared nanovector, we demonstrated the plasmids could be efficiently transfected into tumor cells (~ 63% ± 4%) in a time-controlled manner, and that functional CRISPR/Cas9 proteins could be successfully expressed in a selected NIR-irradiated region. Particularly, this strategy was successfully applied to the delivery of CRISPR/Cas9 gene to tumor cells in vivo, inducing high efficiency editing of the target gene PLK-1 under photoirradiation. Therefore, this precisely controlled gene regulation strategy has the potential to serve as a new paradigm for gene engineering in complex biological systems.

Cellular redox status presents broad implications with diverse physiological and pathological processes. Simultaneous detection of both the oxidative and reductive species of redox couples, especially the most representative pair glutathione/hydrogen peroxide (GSH/H₂O₂), is crucial to accurately map the cellular redox status. However, it still remains challenging to synchronously detect GSH/H₂O₂ in vivo due to lack of a reliable measuring tool. Herein, a ratiometric nanoprobe (UCNP-TB) possessing simultaneous delectability of GSH/H₂O₂ is established based on a multi-spectral upconverting nanophosphor (UCNP-OA) as the luminescence resonance energy transfer (LRET) donor and two dye molecules as the acceptors, including a GSH-sensitive dye (TCG) and a H₂O₂-sensitive dye (BCH). With the as-prepared UCNP-TB, real-time and synchronous monitoring the variation of GSH and H₂O₂ in vitro and in living mice can be achieved using the ratio of the upconversion luminescence (UCL) at 540 and 650 nm to that at 800 nm as the detection signal, respectively, providing highly inherent reliability of the sensing results by self-calibration. Moreover, the nanoprobe is capable of mapping the redox status within the drug-resistant tumor and the drug-induced hepatotoxic liver via ratiometric UCL imaging. Thus, this nanoprobe would provide a reliable tool to elucidate the redox state in vivo.