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Activatable type I photosensitizers are an effective way to overcome the insufficiency and imprecision of photodynamic therapy in the treatment of hypoxic tumors, however, the incompletely inhibited photoactivity of pro-photosensitizer and the limited oxidative phototoxicity of post-photosensitizer are major limitations. It is still a great challenge to address these issues using a single and facile design. Herein, a series of totally caged type I pro-photosensitizers (Pro-I-PSs) are rationally developed that are only activated in tumor hypoxic environment and combine two oxygen-independent therapeutic mechanisms under single-pulse laser irradiation to enhance the phototherapeutic efficacy. Specifically, five benzophenothiazine-based dyes modified with different nitroaromatic groups, BPN 1-5, are designed and explored as latent hypoxia-activatable Pro-I-PSs. By comparing their optical responses to nitroreductase (NTR), it is identified that the 2-methoxy-4-nitrophenyl decorated dye (BPN 2) is the optimal Pro-I-PSs, which can achieve NTR-activated background-free fluorescence/photoacoustic dual-modality tumor imaging. Furthermore, upon activation, BPN 2 can simultaneously produce an oxygen-independent photoacoustic cavitation effect and a photodynamic type I process at single-pulse laser irradiation. Detailed studies in vitro and in vivo indicated that BPN 2 can effectively induce cancer cell apoptosis through synergistic effects. This study provides promising potential for overcoming the pitfalls of hypoxic-tumor photodynamic therapy.

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We report a method for fast Fourier transform (FFT)-weighted optical coherence tomography (OCT) in the second biological tissue transparency window by actively modulating the plasmonic scattering of Fe3O4@Au hybrid nanorods using magnetic fields. Instead of tracking the nanoparticles' lateral displacement in conventional magnetomotive OCT imaging, we monitor the nanorod rotation and optical signal changes under an alternating magnetic field in real time. The coherent rotation of the nanorods with the field produces periodic OCT signals, and the FFT is then used to convert the periodic OCT signals in the time domain to a single peak in the frequency domain. This allows automatic screening of nanorod signals from the random biological noises and reconstruction of FFT-weighted images using a computer program based on a time-sequence image set. Compared with conventional magnetomotive OCT, the FFT-weighted imaging technique creates enhanced OCT images with dB-scale contrast over an order of magnitude higher than the original images.

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Photoacoustic (PA) imaging uses photon-phonon conversion for high-resolution tomography of biological tissues and functions. Exogenous contrast agents are often added to improve the image quality, but the interference from endogenous molecules diminishes the imaging sensitivity and specificity. We report a background-free PA imaging technique based on the active modulation of PA signals via magnetic alignment of Fe3O4@Au hybrid nanorods. Switching the field direction creates enhanced and deactivated PA imaging modalities, enabling a simple pixel subtraction to effectively minimize background noises. Under an alternating magnetic field, the nanorods exhibit PA signals of coherently periodic changes that can be converted into a sharp peak in a frequency domain via the fast Fourier transform. Automatic pixel-wise screening of nanorod signals performed using a computational algorithm across a time-sequence set of PA images regenerates a background-free PA image with significantly improved contrast, specificity, and fidelity.

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To address the growing demand for simultaneous imaging of multiple biomarkers in highly scattering media such as organotypic cell cultures, we introduce a new type of photoluminescent nanomaterial termed "tau-ruby" composed of ruby nanocrystals (Al2O3:Cr3+) with tunable emission lifetime. The lifetime tuning range from 2.4 to 3.2 ms was achieved by varying the Cr3+ dopant concentration from 0.8% to 0.2%, affording facile implementation of background-free detection. We developed inexpensive scalable production of tau-ruby characterized by bright emission, narrow spectrum (693 ± 2 nm), and virtually unlimited photostability upon excitation with affordable excitation/detection sources, noncytotoxic and insensitive to microenvironmental fluctuations. By functionalizing the surface of tau-rubies with targeting antibodies, we obtained different biomarkers suitable for multiplexed lifetime imaging. As a proof of principle, three tau-ruby bioprobes, characterized by three mean lifetimes, were deployed to label three µ-opioid receptor species expressed on transfected cancer cells, each fused to a unique epitope, so that three types of cells were lifetime-encoded. Robust decoding of photoluminescent signals that report on each cell type was achieved by using a home-built lifetime imaging system and resulted in high-contrast multiplexed lifetime imaging of the cells.

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There is an immense literature on detection of latent fingerprints (LFPs) with fluorescent nanomaterials because fluorescence is one of the most sensitive detection methods. Although many fluorescent probes have been developed for latent fingerprint detection, many challenges remain, including the low selectivity, complicated processing, high background, and toxicity of nanoparticles used to visualize LFPs. In this study, we demonstrate biocompatible, efficient, and low background LFP detection with poly(vinylpyrrolidone) (PVP) coated fluorescent nanodiamonds (FNDs). PVP-coated FND (FND@PVP) is biocompatible at the cellular level. They neither inhibit cellar proliferation nor induce cell death via apoptosis or other cell killing pathways. Moreover, they do not elicit an immune response in cells. PVP coating enhances the physical adhesion of FND to diverse substrates and in particular results in efficient binding of FND@PVP to fingerprint ridges due to the intrinsic amphiphilicity of PVP. Clear, well-defined ridge structures with first, second, and third-level of LFP details are revealed within minutes by FND@PVP. The combination of this binding specificity and the remarkable optical properties of FND@PVP permits the detection of LPFs with high contrast, efficiency, selectivity, sensitivity, and reduced background interference. Our results demonstrate that background-free imaging via multicolor emission and dual-modal imaging of FND@PVP nanoparticles have great potential for high-resolution imaging of LFPs.

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Photoacoustic (PA) imaging based on the photon-to-ultrasound conversion allows the imaging of optical absorbers in deep tissues with high spatial resolution. However, the inherent optical absorbance of biomolecules (e.g., hemoglobin, melanin, etc.) would show up as tissue background signals to interfere with signals from the contrast agent during in vivo PA imaging, limiting the imaging sensitivity. Herein, an ultrasound (US)-responsive PA imaging probe based on microbubbles (MBs) containing gold nanoparticles (Au NPs) is designed for in vivo "background-free" PA imaging. The obtained Au@lip MBs with separated Au NPs decorated within the lipid shell of MBs show low PA signals under near-infrared (NIR) excitation. Interestingly, under exposure to US pulses, those Au@lip MBs would burst to form nanoscale aggregates of Au@lip NPs, which exhibit significantly enhanced NIR PA signals due to their red-shifted surface plasmon resonance. Therefore, by subtracting the PA image captured pre-US burst from that captured post-US burst, the tissue background PA signals could be deducted to enable background-free PA imaging with high sensitivities as demonstrated by multiple ex vivo and in vivo experiments. This work presents a simple yet effective strategy to deduct background signals during PA imaging, which is promising for accurate PA detection of targets in tissues with a strong background.

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Lanthanide-doped photon-upconversion nanoparticles (UCNPs) have been the focus of many research activities in materials and life sciences in the last 15 years because of their potential to convert light between different spectral regions and their unique photophysical properties. To fully exploit the application potential of these fascinating nanomaterials, a number of challenges have to be overcome, such as the low brightness, particularly of small UCNPs, and the reliable quantification of the excitation-power-density-dependent upconversion luminescence. In this series of critical reviews, recent developments in the design, synthesis, optical-spectroscopic characterization, and application of UCNPs are presented with special focus on bioanalysis and the life sciences. Here we guide the reader from the synthesis of UCNPs to different concepts to enhance their luminescence, including the required optical-spectroscopic assessment to quantify material performance; surface modification strategies and bioanalytical applications as well as selected examples of the use of UCNPs as reporters in different assay formats are addressed in part II. Future trends and challenges in the field of upconversion are discussed with special emphasis on UCNP synthesis and material characterization, particularly quantitative luminescence studies. Graphical Abstract Both synthesis and spectroscopy as well bioanalytical applications of UCNPs are driven and supported by COST Action CM1403 "The European Upconversion Network".

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In Part II of this review series on lanthanide-doped photon-upconversion nanoparticles (UCNPs), we present and critically discuss the performance and suitability of UCNPs as background-free luminescent reporters in bioimaging and bioanalytical applications. The preparation of a biocompatible nanoparticle surface is an integral step for all life - science-related applications. UCNPs have found their way into a large number of diagnostic platforms, homogeneous and heterogeneous assay formats, and sensor applications. Many bioanalytical detection schemes involve Förster resonance energy transfer (FRET), which is still debated for UCNPs and needs to be much improved. The need for dedicated and standardized instruments as well as recent studies on the dissolution and potential toxicity of UCNPs are addressed. Finally we outline future trends and challenges in the field of upconversion. Graphical Abstract Both synthesis / spectroscopy as well bioanalytical applications of UCNPs are driven by the COST Action CM1403 "The European Upconversion Network".

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