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Chemodynamic therapy (CDT) is a highly tumor-specific treatment, while its efficacy is compromised by the intratumoral Fenton reaction efficiency, which is determined by the following reaction factors, including the availability of Fenton ions (e.g., Fe2+), the amount of H2O2, and the degree of acidity. Synchronous optimization of these factors is a big challenge for efficient CDT. Herein, a strategy of comprehensively optimizing Fenton reaction factors was developed for traceable multistage augmented CDT by charge-reversal theranostics. The customized pH-responsive poly(ethylene)glycol-poly(β-amino esters) (PEG–PAE) micelle (PM) was prepared as the carrier. Glucose oxidase (GOx), Fe2+, and pH-responsive second near-infrared (NIR-II) LET-1052 probe were coloaded by PM to obtain the final theranostics. The activity of metastable Fe2+remained by the unsaturated coordination with PEG–PAE. Then tumor accumulation and exposure of Fe2+were achieved by charge-reversal cationization of PEG–PAE, which was further enhanced by a GOx catalysis-triggered pH decrease. Together with the abundant H2O2generation and pH decrease through GOx catalysis, the limiting factors of the Fenton reaction were comprehensively optimized, achieving the enhanced CDT both in vitroand in vivo. These findings provide a strategy for comprehensively optimizing intratumoral Fenton reaction factors to overcome the intrinsic drawbacks of current CDT.

Oxidative stress and a series of excessive inflammatory responses are major obstacles for neurological functional recovery after ischemic stroke. Effective noninvasive anti-inflammatory therapies are urgently needed. However, unsatisfactory therapeutic efficacy of current drugs and inadequate drug delivery to the damaged brain are major problems. Nanozymes with robust anti-inflammatory and antioxidative stress properties possess therapeutic possibility for ischemic stroke. However, insufficiency of nanozyme accumulation in the ischemic brain by noninvasive administration hindered their application. Herein, we report a neutrophil-like cell-membrane-coated mesoporous Prussian blue nanozyme (MPBzyme@NCM) to realize noninvasive active-targeting therapy for ischemic stroke by improving the delivery of a nanozyme to the damaged brain based on the innate connection between inflamed brain microvascular endothelial cells and neutrophils after stroke. The long-term in vivotherapeutic efficacy of MPBzyme@NCM for ischemic stroke was illustrated in detail after being delivered into the damaged brain and uptake by microglia. Moreover, the detailed mechanism of ischemic stroke therapy viaMPBzyme@NCM uptake by microglia was further studied, including microglia polarization toward M2, reduced recruitment of neutrophils, decreased apoptosis of neurons, and proliferation of neural stem cells, neuronal precursors, and neurons. This strategy may provide an applicative perspective for nanozyme therapy in brain diseases.

Fluorescence imaging has made tremendous inroads toward understanding the complexity of biological systems, but in vivo deep-tissue imaging remains a great challenge due to the optical opacity of biological tissue. Recent improvements in laser and detector manufacturing have allowed the expansion of nonlinear and linear fluorescence imaging to the underexplored “tissue-transparent” second near-infrared (NIR-II; 1000–1700 nm) window, opening up new opportunities for optical access deep inside opaque tissue. Molecular fluorophores have historically played a major role in fluorescence bioimaging. It is increasingly important to design new molecular fluorophores to fully unlock the potential of NIR-II imaging techniques. In this outlook, we give an overview of the novel molecular fluorophores developed for deep-tissue bioimaging in the past five years and discuss their pros and cons in applications. Guidelines for designing new molecular fluorophores with the desirable properties are also provided.

Light in the second near-infrared window, especially beyond 1500 nm, shows enhanced tissue transparency for high-resolution in vivooptical bioimaging due to decreased tissue scattering, absorption, and autofluorescence. Despite some inorganic luminescent nanoparticles have been developed to improve the bioimaging around 1500 nm, it is still a great challenge to synthesize organic molecules with the absorption and emission toward this region. Here, we present J-aggregates with 1360 nm absorption and 1370 nm emission formed by self-assembly of amphiphilic cyanine dye FD-1080 and 1,2-dimyristoyl-sn-glycero-3-phosphocholine. Molecular dynamics simulations were further employed to illustrate the self-assembly process. Superior spatial resolution and high signal-to-background ratio of J-aggregates were demonstrated for noninvasive brain and hindlimb vasculature bioimaging beyond 1500 nm. The efficacy evaluation of the clinically used hypotensor is successfully achieved by high-resolution in vivodynamic vascular imaging with J-aggregates.

The near‐infrared range (NIR, 700−1700 nm) has been used as a superior optical window for non‐invasive bioimaging. Increasing signal‐to‐noise ratio (SNR) is the most fundamental method to improve NIR bioimaging. However, the low delivery efficiency of fluorescent contrast agents leads to weak signal at lesions. Moreover, non‐specific accumulation and “always on” signals will cause “false positive” signals and high background noise, all of which result in low SNR and potential long‐term biotoxicity. Thus, to reach precise detection of lesions, strong bioimaging signals and low background interference are the two important pre‐requisites. This review provides an overview of in vivo assembly and disassembly strategies to improve tumor‐specific accumulation, “turn‐on” the silent signals, and reduce the background noise in NIR bioimaging windows. In vivo assembly and disassembly occurring spontaneously, responding to disease micro‐environment or external stimuli, including pH, enzymes, reactive oxygen species, redox, light, and specific recognition is summarized, which may provide ideas and approaches to further enhance bioimaging and reduce long‐term biotoxicity concerns. This paper overviews in vivo assembly and disassembly strategiesto improve tumor‐specific accumulation, “turn‐on” the silent signals and reduce the background noise in near‐infrared bioimaging window. In vivo assembly and disassembly occurring spontaneously, responding to disease micro‐environment or external stimulus is summarized, which may provide ideas and approaches to further enhance bioimaging and reduce long‐term biotoxicity concern.