Simultaneously acquiring chemical and topographical information within asingle cell at nanoscale resolutions is vital to cellular biology,yet it remains agreat challenge due to limited lateral resolutions and detection sensitivities.H erein, the development of near-field desorption mass spectrometry for correlated chemical and topographical imaging is reported, therebyb ridging the gap between laser-based mass spectrometry (MS) methods and multimodal single-cell imaging.Using this integrated platform, an imaging resolution of 250 nm and 3D topographically reconstructed chemical single-cell imaging were achieved.T his technique offers more in-depth cellular information than micrometer-range laser-based MS imaging methods.C onsidering the simplicity and compact sizeo ft he near-field device,this techniquecan be introduced to MALDI-MS,e xpanding the multimodal abilities of MS at nanoscale resolutions.

In order to achieve safe and high-efficient photodynamic therapy (PDT), it was a powerful strategy of constructing O 2 -generated nanozyme with intelligent "off/on" modulation and enhancement. Herein, a kind of H 2 O 2 -responsive nanozyme was developed for off/on modulation and enhancement of magnetic resonance (MR) imaging and PDT, in which great amounts of gold nanoclusters (AuNCs) were loaded into mesoporous silica to form nanoassembly, and manganese dioxide (MnO 2 ) nanosheets were wrapped as switching shield shell (AuNCs@mSiO 2 @MnO 2 ). In a neutral physiological environment, stable MnO 2 shells eliminated singlet oxygen ( 1 O 2 ) generation to switch off PDT and MR imaging. However, in an acidic tumor microenvironment, the MnO 2 shell reacted with H 2 O 2 , in which MnO 2 degradation switched on MR imaging and PDT, and the generated O 2 further enhanced PDT. H 2 O 2 -responsive MnO 2 degradation brought about excellent MR imaging with a longitudinal relaxation rate of 25.31 mM −1 s −1 , and simultaneously sufficient O 2 generation guaranteed a 74% high 1 O 2 yield. Under the irradiation of a 635 nm laser, the viability of MDA-MB-435 cells was reduced to 4%, and the tumors completely disappeared, demonstrating strong PDT performance. Therefore, H 2 O 2 -responsive AuNCs@mSiO 2 @MnO 2 nanozyme showed excellent off/on modulation and enhancement of MR imaging and PDT and was a promising intelligent nanoprobe for safe and high-efficiency theranostics.

Light-responsive nanoprobes were suffering from the threat of high-dose laser irradiation, and it was important for constructing new nanoprobes for safe and efficient phototheranostics. Here, polydopamine (PDA)-coated gold nanobipyramids (AuNBPs@PDA) were synthesized for amplified photoacoustic (PA) signal and enhanced photothermal conversion with low-dose laser irradiation and then doxorubicin (DOX)-loaded AuNBPs@PDA–DOX nanoprobes were constructed for PA imaging-guided synergistic photothermal therapy (PTT) and chemotherapy. The AuNBPs@PDA nanoparticles possessed higher photothermal conversion efficiency (42.07%) and stronger PA signal than those of AuNBP nanoparticles, and the AuNBPs@PDA–DOX nanoprobes showed dual-responsive DOX release of pH and photothermal stimulation. With low-dose laser irradiation (1.0 W/cm2) and low-concentration AuNBPs@PDA–DOX (60 μg/mL), the 4T1 cell viability was reduced to about 5%, owing to the combination of PTT and chemotherapy, compared with 42.3% of single chemotherapy and 25.3% of single PTT. Moreover, by modeling 4T1 tumor-bearing nude mice, in vivo PA imaging was achieved and the tumors were completely inhibited, demonstrating the excellent synergistic effect of PTT/chemotherapy. Therefore, the developed AuNBPs@PDA–DOX nanoprobes can be used for phototheranostics and synergistic chemotherapy, achieving low-dose laser irradiation and high-efficient visualized theranostics.

The visualization of temporal and spatial changes in the intracellular environment has great significance for chemistry and bioscience research. Mass spectrometry imaging (MSI) plays an important role because of its unique advantages, such as being label‐free and high throughput, yet it is a challenge for laser‐based techniques due to limited lateral resolution. Here, we develop a simple, reliable, and economic nanoscale MSI approach by introducing desorption laser with a micro‐lensed fiber. Using this integrated platform, we achieved 300 nm resolution MSI and successfully visualized the distribution of various small‐molecule drugs in subcellular locations. Exhaustive dynamic processes of anticancer drugs, including releasing from nanoparticle carriers entering nucleus of cells, can be readily acquired on an organelle scale. Considering the simplicity and universality of this nanoscale desorption device, it could be easily adapted to most of laser‐based mass spectrometry applications.

Mass spectrometry imaging (MSI) has become a powerful tool in diverse fields, such as chemistry, physics, materials, and life science. Although such research is getting more prevalent, it is limited by high-resolution (HR) instrumental development. Recently, unceasing efforts have been made toward taking spatial resolution from the microscale to nanoscale, especially for near-field based techniques. These emerging and unique features behind high-resolution mass spectrometry imaging (HR-MSI) provide new possibilities in various aspects of biological researches. Since many technological advances provided a forefront for HR-MSI, compelling challenges including sensitivity, specificity, multimodal imaging, data acquisition, and processing follow undoubtedly. Gratifyingly, with attempts and experiences in the infancy, the emerging techniques move toward much more mature to deal with underlying conundrums in the future. Not only confined to commercial instruments, this perspective highlights recent innovations covering all emerging HR-MSI (with spatial resolution below 5 μm) techniques. Besides, vital limitations and handicaps at this stage are presented while corresponding schemes are proposed. This perspective also gives the authors’ personal outlooks of developments and applications for HR-MSI in coming years.