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Objective: Checkpoint immunotherapy unleashes T-cell control of tumours but is suppressed by immunosuppressive myeloid cells. The transmembrane protein MS4A4A is selectively highly expressed in tumour-associated macrophages (TAMs). Here, we aimed to reveal the role of MS4A4A + TAMs in regulating the immune escape of tumour cells and to develop novel therapeutic strategies targeting TAMs to enhance the efficacy of immune checkpoint inhibitor (ICI) in colorectal cancer., Design: The inhibitory effect of MS4A4A blockade alone or combined with ICI treatment on tumour growth was assessed using murine subcutaneous tumour or orthotopic transplanted models. The effect of MS4A4A blockade on the tumour immune microenvironment was assessed by flow cytometry and mass cytometry. RNA sequencing and western blot analysis were used to further explore the molecular mechanism by which MS4A4A promoted macrophages M2 polarisation., Results: MS4A4A is selectively expressed by TAMs in different types of tumours, and was associated with adverse clinical outcome in patients with cancer. In vivo inhibition of MS4A4A and anti-MS4A4A monoclonal antibody treatment both curb tumour growth and improve the effect of ICI therapy. MS4A4A blockade treatment reshaped the tumour immune microenvironment, resulting in reducing the infiltration of M2-TAMs and exhausted T cells, and increasing the infiltration of effector CD8 + T cells. Anti-MS4A4A plus anti-programmed cell death protein 1 (PD-1) therapy remained effective in large, treatment-resistant tumours and could induce complete regression when further combined with radiotherapy. Mechanistically, MS4A4A promoted M2 polarisation of macrophages by activating PI3K/AKT pathway and JAK/STAT6 pathway., Conclusion: Targeting MS4A4A could enhance the ICI efficacy and represent a new anticancer immunotherapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

225 Ac is considered as one of the most promising radioisotopes for alpha-therapy because its emitted high-energy α-particles can efficiently damage tumor cells. However, it also represents a significant threat to healthy tissues owing to extremely high radiotoxicity if targeted therapy fails. This calls for a pressing requirement of monitoring the biodistribution of 225 Ac in vivo during the treatment of tumors. However, the lack of imageable photons or positrons from therapeutic doses of 225 Ac makes this task currently quite challenging. We report here a nanoscale luminescent europium-organic framework (EuMOF) that allows for fast, simple, and efficient labeling of 225 Ac in its crystal structure with sufficient 225 Ac-retention stability based on similar coordination behaviors between Ac 3+ and Eu 3+ . After labeling, the short distance between 225 Ac and Eu 3+ in the structure leads to exceedingly efficient energy transduction from 225 Ac-emitted α-particles to surrounding Eu 3+ ions, which emits red luminescence through a scintillation process and produces sufficient photons for clearcut imaging. The in vivo intensity distribution of radioluminescence signal originating from the 225 Ac-labeled EuMOF is consistent with the dose of 225 Ac dispersed among the various organs determined by the radioanalytical measurement ex vivo , certifying the feasibility of in vivo directly monitoring 225 Ac using optical imaging for the first time. In addition, 225 Ac-labeled EuMOF displays notable efficiency in treating the tumor. These results provide a general design principle for fabricating 225 Ac-labeled radiopharmaceuticals with imaging photons and propose a simple way to in vivo track radionuclides with no imaging photons, including but not limited to 225 Ac.

The peptidyl arginine deiminase (PADI) family is a calcium ion-dependent group of isozymes with sequence similarity that catalyze the citrullination of proteins. Histones can serve as the target substrate of PADI family isozymes, and therefore, the PADI family is involved in NETosis and the secretion of inflammatory cytokines. Thus, the PADI family is associated with the development of inflammatory autoimmune diseases and cancer, reproductive development, and other related diseases. In this review, we systematically discuss the role of the PADI family in the pathogenesis of various diseases based on studies from the past decade to provide a reference for future research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhu, Liu and Chai.)

Measuring the changes in tumor cell surface temperature can provide insights into cellular metabolism and pathological features, which is significant for targeted chemotherapy and hyperthermic therapy. However, conventional micro-nano scale methods are invasive and can only measure the temperature of cells across a single plane, which excludes specific organelles. In this study, fluorescence quantum dots (QDs) are functionalized with the membrane transport protein transferrin (Tf) as a thermo-sensor specific for tumor cell membrane. The covalent conjugation is optimized to maintain the relative fluorescence intensity of the Tf-QDs to >90%. In addition, the Tf-QDs undergo changes in the fluorescence spectra as a function of temperature, underscoring its thermo-sensor function. Double helix point spread function imaging optical path is designed to locate the probe at nanoscale, and 3D thermal imaging technology is proposed to measure the local temperature distribution and direction of heat flux on the tumor cell surface. This novel targeted nanoscale 3D thermometry method can be a highly promising tool for measuring the local and global temperature distribution across intracellular organelles., (© 2021 Wiley-VCH GmbH.)

Specific and effective accumulation of nanoparticles within tumors is highly crucial for precise cancer diagnosis and treatment. Therefore, spatiotemporally manipulating the aggregation of small gold nanoparticles (AuNPs) in a tumor microenvironment is of great significance for enhancing the diagnostic and therapeutic efficacy of tumors. Herein, we reported a novel furin enzyme/acidic pH synergistically triggered small AuNP aggregation strategy for activating the photoacoustic (PA) imaging and photothermal (PTT) functions of AuNPs in vivo. Smart gold nanoparticles decorated with furin-cleavable RVRR (Arg-Val-Arg-Arg) peptides (Au-RRVR) were rationally designed and fabricated. Both in vitro and in vivo experiments demonstrated that such Au-RRVR nanoparticles could be simultaneously induced by furin and acidic pH to form large aggregates within tumorous tissue resulting in improved tumor accumulation and retention, which can further activate the PA and PTT effect of AuNPs for sensitive imaging and efficient therapy of tumors. Thus, we believe that this dual-stimuli-responsive aggregation system may offer a universal platform for effective cancer diagnosis and treatment.

We discovered that attenuated Salmonella after intravenous injection would proliferate within various types of solid tumors but show rapid clearance in normal organs, without rendering notable toxicity. Bacteria-induced inflammation would trigger thrombosis in the infected tumors by destroying tumor blood vessels. Six types of tested tumors would all turn into darkened color with strong near-infrared absorbance, as observed by photoacoustic imaging. Under laser irradiation, those bacterial-infected tumors would be effectively ablated. Because of the immune-stimulation function, such bacteria-based photothermal therapy (PTT) would subsequently trigger antitumor immune responses, which could be further enhanced by immune checkpoint blockade to effectively suppress the growth of abscopal tumors. A robust immune memory effect to reject rechallenged tumors is also observed after bacteria-based PTT. Our work demonstrates that bacteria by themselves could act as a tumor-specific PTT agent to enable photoimmunotherapy cancer therapy to inhibit tumor metastasis and recurrence., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Mitochondrial targeting of drugs largely relies on delocalized lipophilic cations. Nevertheless, mitochondrial membrane potentials in cancer cells are inconstant, which could compromise stable mitochondrial targeting. Herein, we further validated a mitochondrial temperature-dependent drug delivery strategy in vivo. Thermoresponsive drug delivery to mitochondria may represent a promising strategy for cancer therapy.

Mitochondria emerge as an important target for cancer therapy. Herein, by taking advantage of the recently reported high temperature of mitochondria, a well-tuned thermoresponsive nanocarrier was developed for specifically delivering the anticancer drug, paclitaxel (PTX), to mitochondria in cancer cells. The temperature-dependent delivery of drugs to mitochondria represents a novel anticancer strategy.

Exploiting ultrasmall nanoparticles as multifunctional nanocarriers labeled with different radionuclides for tumor theranostics has attracted great attention in past few years. Herein, we develop multifunctional nanocarriers based on ultrasmall hyperbranched semiconducting polymer (HSP) nanoparticles for different radionuclides including technetium-99m ( 99m Tc), iodine-131 ( 131 I), and iodine-125 ( 125 I) labeling. SPECT imaging of 99m Tc labeled PEGylated HSP nanoparticles (HSP-PEG) exhibit a prominent accumulation in two-independent tumor models including subcutaneously xenograft and patient derived xenograft model. Impressively, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), as tumor-vascular disrupting agent (VDA), significantly improves the tumor accumulation of 131 I labeled HSP-PEG nanoparticles, further leading to the excellent inhibition of tumor growth after intravenous injection. More importantly, SPECT imaging of 125 I labeled HSP-PEG indicates that ultrasmall HSP-PEG nanoparticles could be slowly excreted from the body of a mouse through urine and feces in 1 week and cause no obvious toxicity to treated mice from blood analysis and histology examinations. Our finding from the different independent tumor models SPECT imaging shows that HSP-PEG nanoparticles may act as multifunctional nanocarriers to deliver different radionuclides for monitoring the in vivo behaviors of nanoparticles and cancer theranostics, which will provide a strategy for cancer treatment.

Rare cancer cells in body fluid could be useful biomarkers for noninvasive diagnosis of cancer. However, detection of these rare cells is currently challenging. In this work, a binding-induced dual catalytic hairpin assembly (DCHA) electrochemical cytosensor was developed for highly selective and sensitive detection of cancer cells. The fuel probe, released by hybridization between the capture probe and catalytic hairpin assembly (CHA) products of target cell-responsive reaction, initiated dual CHA recycling, leading to multiple CHA products. Furthermore, the hybridization between fuel probe and capture probe decreased non-specific CHA products, improving the signal-to-noise ratio and detection sensitivity. Under the optimal conditions, the developed cytosensor was able to detect cells down to 30 cells mL -1 (S/N = 3) with a linear range from 50 to 100,000 cells mL -1 and was capable of distinguishing target cells from normal cells in clinical blood samples., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Metallomics, focusing on the global and systematic understanding of the metal uptake, trafficking, role, and excretion in biological systems, has attracted more and more attention. Metal-related nanomaterials, including metallic and metal-containing nanomaterials, have unique properties compared to their macroscale counterparts and therefore require special attention. The absorption, distribution, metabolism, excretion (ADME) behavior of metal-related nanomaterials in the biological systems is influenced by their physicochemical properties, the exposure route, and the microenvironment of the deposition site. Nanomaterials not only may interact directly or indirectly with genes, proteins, and other molecules to bring genotoxicity, immunotoxicity, DNA damage, and cytotoxicity but may also stimulate the immune responses, circumvent tumor resistance, and inhibit tumor metastasis. Because of their advantages of absolute quantification, high sensitivity, excellent accuracy and precision, low matrix effects, and nondestructiveness, nuclear and related analytical techniques have been playing important roles in the study of metallomics and nanometallomics. In this chapter, we present a comprehensive overview of nuclear and related analytical techniques applied to the quantification of metallome and nanometallome, the biodistribution, bioaccumulation, and transformation of metallome and nanometallome in vivo, and the structural analysis. Besides, metallomics and nanometallomics need to cooperate with other -omics, like genomics, proteomics, and metabolomics, to obtain the knowledge of underlying mechanisms and therefore to improve the application performance and to reduce the potential risk of metallome and nanometallome.

Phototherapy, as a noninvasive therapeutic procedure, has been applied to treat tumors. However, the application of phototherapy is often compromised by its low efficiency. Herein, we developed a novel nanoplatform based on cationic amphiphilic polymer-wrapped carbon nanotubes (rPAA@SWCNTs) with a photosensitizer, indocyanine green (ICG), for phototherapy. The as-prepared nanoparticles exhibited excellent mitochondria targeting due to the synergistic properties of highly positive charges from the polycations on the corona and the high hydrophobicity from the carbon nanotubes in the core. Moreover, the high buffer capacity of the polycations facilitated the endosomal escape of nanoparticles via a proton-sponge effect. When irradiated with an 808 nm NIR laser, ICG/rPAA@SWCNTs could precisely damage mitochondria with high efficiency and produce reactive oxygen species (ROS) and hyperthermia, which further induced the ROS burst from damaged mitochondria. The overproduced ROS accumulated in mitochondria ultimately resulted in mitochondrial damage and cell death. Therefore ICG/rPAA@SWCNTs may be able to achieve an amplifying phototherapeutic effect.

Accumulation of nanoparticles in solid tumors depends on their extravasation, but their efficacy is often compromised by intrinsic physiological heterogeneity in tumors. The conventional solutions to circumvent this problem are size control of nanoparticles or increasing the vascular permeability. The aim of this study is to investigate the combination effect of size variation of stimuli-responsive nanoparticles and improved vascular permeability triggered by near-infrared (NIR) light irradiation. Doxorubicin (DOX), a clinically proven drug for bladder cancer, was encapsulated in the nanocomposites with high loading content up to 45%. We show that NIR light-responsive size-switchable nanocarriers could considerably enhance the tumor-targeting of DOX in bladder tumor-bearing mice. Moreover, a combination of NIR-induced hyperthermia and DOX-mediated chemotherapy resulted in remarkable inhibition of tumor growth in mice. Histological results suggest that the change in morphology of tumor microvasculature may account for enhanced extravasation and accumulation of the nanodrugs upon NIR irradiation. Together, these data suggest that external stimuli-responsive drug delivery system offers a safe and effective means of targeted chemo/photothermal therapy.

Although conventional radiotherapy (RT) has been widely used in the clinic to treat cancer, it often has limited therapeutic outcomes and severe toxic effects. There is still a need to develop theranostic agents with both imaging and RT-enhancing functions to improve the accuracy and efficiency of RT. Herein we synthesize Au@MnS@ZnS core/shell/shell nanoparticles with polyethylene glycol (PEG) functionalization, yielding Au@MnS@ZnS-PEG nanoparticles with great stability in different physiological solutions and no significant cytotoxicity. It is found that Au@MnS@ZnS-PEG nanoparticles can enhance the cancer cell killing efficiency induced by RT, as evidenced by multiple in vitro assays. Owing to the existence of paramagnetic Mn(2+) in the nanoparticle shell, our Au@MnS@ZnS-PEG can be used as a contrast agent for T1-weighted magnetic resonance (MR) imaging, which reveals the efficient accumulation and retention of nanoparticles in the tumors of mice after intravenous injection. Importantly, by exposing tumor-bearing mice that were injected with Au@MnS@ZnS-PEG to X-ray irradiation, the tumor growth can be significantly inhibited. This result shows clearly improved therapeutic efficacy compared to RT alone. Furthermore, no obvious side effect of Au@MnS@ZnS-PEG is observed in the injected mice. Therefore, our work presents a new type of radiosensitizing agent, which is promising for the imaging-guided enhanced RT treatment of cancer.

Engineered gold nanoparticles (AuNPs) have recently drawn an increased interest in disease diagnostics and therapies. However, reports on detailed studies of AuNPs regarding their pharmacodynamics, pharmacokinetics, biodistribution, metabolism and potential toxicity are limited. It is common knowledge that the in vivo behavior and fate of various AuNPs are influenced by their surface and size. However, a comprehensive description and understanding of all variables is crucial for their further development toward potential clinical use. In this article, we describe the pharmacokinetics and biodistribution of mesoporous silica-coated gold nanorods functionalized with polyethylene glycol or bovine serum albumin (AuNR@SiO2-PEG and AuNR@SiO2-BSA, respectively) in tumor-bearing balb/c mice. To gain further insight into the pharmacokinetics, biodistribution and tumor uptake, we also compare the results with BSA functionalized gold nanorods (AuNR-BSA) and gold clusters (AuNC-BSA). The results reveal that AuNR@SiO2-PEG have the longest blood half-life and the maximum percentage content in the tumor at 24 h and 3 days compared to other AuNPs. AuNR@SiO2-PEG, AuNR@SiO2-BSA and AuNR-BSA had primarily accumulated in the liver and spleen without apparent metabolism after 3 days, while the content of AuNC-BSA in the liver, spleen and kidneys showed an obvious decrease, indicating a size-dependent metabolism process. Our results demonstrate how to manipulate the size and surface chemistry of AuNPs to prolong their blood circulation time, improve delivery into target organs and achieve a safer design of nanomedicines.

Oxidative stress is considered to be one of the important mechanisms involved in carcinogenesis. In our previous study, gadolinium endohedral metallofullerenol ([Gd@C82(OH)22]n nanoparticles) have shown high inhibitory activity on hepatoma cell (H22) growth in mice. To explore the antioxidative functions of nanoparticles, we investigated the biodistribution of [Gd@C82(OH)22]n nanoparticles, the changes of blood coagulation profiles, the metabolism of reactive oxygen species (ROS) in the tumor-bearing mice as well as the possible relationships between nanoparticles treatment and ROS production in this paper. The activities of hepatic superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), glutathione S-transferase (GST) and catalase (CAT) as well as the levels of reduced glutathione (GSH), protein-bound thiols and malondialdehyde (MDA) were compared between the tumor-bearing mice and normal mice. Transplanted tumors were grown in mice by subcutaneous injection of murine hepatoma cells in the mice. The comparison of the above parameters between nanoparticles and cyclophosphamide (CTX) therapy were also investigated. [Gd@C82(OH)22]n administration can efficiently restore the damaged liver and kidney of the tumor-bearing mice. All the activities of enzymes and other parameters related to oxidative stress were reduced after [Gd@C82(OH)22]n treatment and tended closely to the normal levels. The results suggest that [Gd@C82(OH)22]n nanoparticle treatment could regulate ROS production in vivo.