VP3 protein of Senecavirus A promotes viral IRES-driven translation and attenuates innate immunity by specifically relocalizing hnRNPA2B1.

Viruses deploy sophisticated strategies to hijack the host's translation machinery to favor viral protein synthesis and counteract innate cellular defenses. However, little is known about the mechanisms by which Senecavirus A (SVA) controls the host's translation. Using a series of sophisticated molecular cell manipulation techniques, heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) was identified as an essential host factor involved in translation control in SVA-infected cells. It was also determined that the SVA structural protein, VP3, binds to and relocalizes hnRNPA2B1, which interferes with the host's protein synthesis machinery to establish a cellular environment that facilitates viral propagation via a two-pronged strategy: first, hnRNPA2B1 serves as a potent internal ribosome entry site (IRES) trans-acting factor, which is selectively co-opted to promote viral IRES-driven translation by supporting the assembly of translation initiation complexes. Second, a strong repression of host cell translation occurs in the context of the VP3-hnRNPA2B1 interaction, resulting in attenuation of the interferons response. This is the first study to demonstrate the interaction between SVA VP3 and hnRNPA2B1, and to characterize their key roles in manipulating translation. This novel dual mechanism, which regulates selective mRNA translation and immune evasion of virus-infected cells, highlights the VP3-hnRNPA2B1 complex as a potential target for the development of modified antiviral or oncolytic reagents. IMPORTANCE: Viral reproduction is contingent on viral protein synthesis, which relies entirely on the host's translation machinery. As such, viruses often need to control the cellular translational apparatus to favor viral protein production and avoid host innate defenses. Senecavirus A (SVA) is an important virus, both as an emerging pathogen in the pork industry and as a potential oncolytic virus for neuroendocrine cancers. Here, heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) was identified as a critical regulator of the translational landscape during SVA infection. This study supports a model whereby the VP3 protein of SVA efficiently subverts the host's protein synthesis machinery through its ability to bind to and relocalize hnRNPA2B1, not only selectively promoting viral internal ribosome entry site-driven translation but also resulting in global translation shutdown and immune evasion. Together, these data provide new insights into how the complex interactions between translation machinery, SVA, and innate immunity contribute to the pathogenicity of the SVA.

NeoaPred: a deep-learning framework for predicting immunogenic neoantigen based on surface and structural features of peptide-human leukocyte antigen complexes.

MOTIVATION: Neoantigens, derived from somatic mutations in cancer cells, can elicit anti-tumor immune responses when presented to autologous T cells by human leukocyte antigen. Identifying immunogenic neoantigens is crucial for cancer immunotherapy development. However, the accuracy of current bioinformatic methods remains unsatisfactory. Surface and structural features of peptide-HLA class I (pHLA-I) complexes offer valuable insight into the immunogenicity of neoantigens. RESULTS: We present NeoaPred, a deep-learning framework for neoantigen prediction. NeoaPred accurately constructs pHLA-I complex structures, with 82.37% of the predicted structures showing an RMSD of < 1 Å. Using these structures, NeoaPred integrates differences in surface, structural, and atom group features between the mutant peptide and its wild-type counterpart to predict a foreignness score. This foreignness score is an effective factor for neoantigen prediction, achieving an AUROC (Area Under the Receiver Operating Characteristic Curve) of 0.81 and an AUPRC (Area Under the Precision-Recall Curve) of 0.54 in the test set, outperforming existing methods. AVAILABILITY AND IMPLEMENTATION: The source code is released under an Apache v2.0 license and is available at the GitHub repository (https://github.com/Dulab2020/NeoaPred).

Noninvasive longitudinal PET/CT imaging of CAR T cells using PSMA reporter gene.

PURPOSE: Chimeric antigen receptor (CAR) T cell therapy has achieved great success in treating hematologic malignancies. However, it is yet to prove effective in the treatment of solid tumors. Thus, it is necessary to develop appropriate methodology for the long-term, accurate, and quantitative evaluation of the distribution and activities of CAR T cells in solid tumors. In the present study, we engineered TfR ΔPSMA CAR (CAR-ΔPSMA) T cells, which targeted the transferrin receptor (TfR) expressed by tumor cells and could be tracked in vivo via a reporter gene encoding the truncated prostate specific membrane antigen (ΔPSMA). We then quantitatively monitored these CAR T cells in vitro and in vivo using [68Ga]Ga-PSMA-617 positron emission tomography (PET)/computed tomography (CT). METHODS: The CAR-ΔPSMA T cells were genetically engineered by transducing T cells with a lentiviral vector encoding TfR41BBζ-T2A-ΔPSMA. Firstly, the target expression, activation, and cytotoxicity of CAR-ΔPSMA T cells were validated in vitro. Secondly, the minimum thresholds of CAR-ΔPSMA T cells detection for [68Ga]Ga-PSMA-617 PET/CT were also determined in vitro and in vivo respectively. Lastly, the feasibility of monitoring the biodistribution and infiltration of CAR-ΔPSMA T cells after systematic administration was evaluated in the breast cancer subcutaneous xenograft model. RESULTS: The CAR-ΔPSMA T cells retained activation and tumor killing capacity after transduction of the ΔPSMA-encoding reporter gene. Next, the CAR-ΔPSMA T cells could be reliably tracked by [68Ga]Ga-PSMA-617 PET/CT, the detection sensitivity of which was 250 cells/mm3 in vitro and 100 cells/mm3 in vivo. Next, the sequential imaging assays revealed that [68Ga]Ga-PSMA-617 PET/CT could be used to specifically visualize ΔPSMA+ CAR T cells at the tumor site. The increase in the [68Ga]Ga-PSMA-617 signal intensity over time allowed us to effectively detect CAR T cells in vivo. CONCLUSION: Our findings preliminarily confirmed that [68Ga]Ga-PSMA-617 PET/CT could reliably detect CAR-ΔPSMA T cells in vitro and in vivo in solid tumors, laying the foundation for the monitoring CAR T cell therapy in the future.

Non-invasive visualization of liver fibrosis with [68Ga]Ga-DOTA-FAPI-04 PET from preclinical insights to clinical translation.

PURPOSE: The reversibility of early liver fibrosis highlights the need for improved early detection and monitoring techniques. Fibroblast activation protein (FAP) is a promising theranostics target significantly upregulated during fibrosis. This preclinical and preliminary clinical study investigated a FAP-targeted probe, gallium-68-labeled FAP inhibitor 04 ([68Ga]Ga-DOTA-FAPI-04), for its capability to visualize liver fibrosis. METHODS: The preclinical study employed [68Ga]Ga-DOTA-FAPI-04 micro-positron emission tomography (PET)/computed tomography (CT) on carbon tetrachloride-induced mice model (n = 34) and olive oil-treated control group (n = 26), followed by validation of the probe's biodistribution. Hepatic uptake was correlated with fibrosis and inflammation levels, quantified through histology and serum assays. FAP and α-smooth muscle actin expression were determined by immunohistochemistry, as well as immunofluorescence. The subsequent clinical trial enrolled 26 patients with suspected or confirmed liver fibrosis to undergo [68Ga]Ga-DOTA-FAPI-04 PET/magnetic resonance imaging or PET/CT. Key endpoints included correlating [68Ga]Ga-DOTA-FAPI-04 uptake with histological inflammation grades and fibrosis stages, and evaluating its diagnostic and differential efficacy compared to established serum markers and liver stiffness measurement (LSM). RESULTS: [68Ga]Ga-DOTA-FAPI-04 mean uptake in mice livers was notably higher than in control mice, increasing from week 6 [0.70 ± 0.11 percentage injected dose per cubic centimeter (%ID/cc)], peaking at week 10 (0.97 ± 0.15%ID/cc) and slightly reducing at week 12 (0.89 ± 0.28%ID/cc). The hepatic biodistribution and FAP expression showed a consistent trend. In the patient cohort, hepatic [68Ga]Ga-DOTA-FAPI-04 uptake presented moderate correlations with inflammation grades (r = 0.517 to 0.584, all P < 0.05) and fibrosis stages (r = 0.653 to 0.698, all P < 0.01). The average SUVmax to background ratio in the liver showed superior discriminative ability, especially between stage 0 and stage 1, outperforming LSM (area under curve 0.984 vs. 0.865). CONCLUSION: [68Ga]Ga-DOTA-FAPI-04 PET shows significant potential for non-invasive visualization and dynamic monitoring of liver fibrosis in both preclinical experiment and preliminary clinical trial, especially outperforming other common clinical indicators in the early stage. TRIAL REGISTRATION: NCT04605939. Registered October 25, 2020, https://clinicaltrials.gov/study/NCT04605939.

Development and Evaluation of DOTA-FAPI-Maleimide as a Novel Radiotracer for Tumor Theranostic with Extended Circulation.

This study aimed to evaluate a novel albumin-binding strategy for addressing the challenge of insufficient tumor retention of fibroblast activation protein inhibitors (FAPIs). Maleimide, a molecule capable of covalent binding to free thiol groups, was modified to conjugate with FAPI-04 in order to enhance its binding to endogenous albumin, resulting in an extended blood circulation half-life and increased tumor uptake. DOTA-FAPI-maleimide was prepared and radiolabeled with Ga-68 and Lu-177, followed by cellular assays, pharmacokinetic analysis, PET/CT, and SPECT/CT imaging to assess the probe distribution in various tumor-bearing models. Radiolabeling of the modified probe was successfully achieved with a radiochemical yield of over 99% and remained stable for 144 h. Cellular assays showed that the ligand concentration required for 50% inhibition of the probe was 1.20 ± 0.31 nM, and the Kd was 0.70 ± 0.07 nM with a Bmax of 7.94 ± 0.16 fmol/cell, indicative of higher specificity and affinity of DOTA-FAPI-maleimide compared to other FAPI-04 variants. In addition, DOTA-FAPI-maleimide exhibited a persistent blood clearance half-life of 7.11 ± 0.34 h. PET/CT images showed a tumor uptake of 2.20 ± 0.44%ID/g at 0.5 h p.i., with a tumor/muscle ratio of 5.64 in HT-1080-FAP tumor-bearing models. SPECT/CT images demonstrated long-lasting tumor retention. At 24 h p.i., the tumor uptake of [177Lu]Lu-DOTA-FAPI-maleimide reached 5.04 ± 1.67%ID/g, with stable tumor retention of 3.40 ± 1.95%ID/g after 4 days p.i. In conclusion, we developed and evaluated the thiol group-attaching strategy, which significantly extended the circulation and tumor retention of the adapted FAPI tracer. We envision its potential application for clinical cancer theranostics.

Nanobiotechnology augmented cancer stem cell guided management of cancer: liquid-biopsy, imaging, and treatment.

Cancer stem cells (CSCs) represent both a key driving force and therapeutic target of tumoral carcinogenesis, tumor evolution, progression, and recurrence. CSC-guided tumor diagnosis, treatment, and surveillance are strategically significant in improving cancer patients' overall survival. Due to the heterogeneity and plasticity of CSCs, high sensitivity, specificity, and outstanding targeting are demanded for CSC detection and targeting. Nanobiotechnologies, including biosensors, nano-probes, contrast enhancers, and drug delivery systems, share identical features required. Implementing these techniques may facilitate the overall performance of CSC detection and targeting. In this review, we focus on some of the most recent advances in how nanobiotechnologies leverage the characteristics of CSC to optimize cancer diagnosis and treatment in liquid biopsy, clinical imaging, and CSC-guided nano-treatment. Specifically, how nanobiotechnologies leverage the attributes of CSC to maximize the detection of circulating tumor DNA, circulating tumor cells, and exosomes, to improve positron emission computed tomography and magnetic resonance imaging, and to enhance the therapeutic effects of cytotoxic therapy, photodynamic therapy, immunotherapy therapy, and radioimmunotherapy are reviewed.

Liver-specific delivery of spherical DNA frameworks for alleviation of hepatic ischemic reperfusion injury.

DNA nanostructures have long been developed for biomedical purposes, but their controlled delivery in vivo proposes a major challenge for disease theranostics. We previously reported that DNA nanostructures on the scales of tens and hundreds nanometers showed preferential renal excretion or kidney retention, allowing for sensitive evaluation and effective protection of kidney function, in response to events such as unilateral ureter obstruction or acute kidney injury. Encouraged by the positive results, we redirected our focus to the liver, specifically targeting organs noticeably lacking DNA materials, to explore the interaction between DNA nanostructures and the liver. Through PET imaging, we identified SDF and M13 as DNA nanostructures exhibiting significant accumulation in the liver among numerous candidates. Initially, we investigated and assessed their biodistribution, toxicity, and immunogenicity in healthy mice, establishing the structure-function relationship of DNA nanostructures in the normal murine. Subsequently, we employed a mouse model of liver ischemia-reperfusion injury (IRI) to validate the nano-bio interactions of SDF and M13 under more challenging pathological conditions. M13 not only exacerbated hepatic oxidative injury but also elevated local apoptosis levels. In contrast, SDF demonstrated remarkable ability to scavenge oxidative responses in the liver, thereby mitigating hepatocyte injury. These compelling results underscore the potential of SDF as a promising therapeutic agent for liver-related conditions. This aimed to elucidate their roles and mechanisms in liver injury, providing a new perspective for the biomedical applications of DNA nanostructures.

The association between dietary zinc intake and osteopenia, osteoporosis in patients with rheumatoid arthritis.

BACKGROUND: Diet has been shown to be associated with rheumatoid arthritis (RA), of which osteoporosis is the most common and important complication, and zinc has been shown to inhibit the inflammatory response, but studies on the relationship between dietary zinc and osteoporosis in patients with RA are limited and inconclusive. In this study, we aimed to explore the relationship between dietary zinc intake and osteoporosis or osteopenia in patients with RA. METHODS: Data on RA patients were derived from the National Health and Nutrition Examination Survey (NHANES) 2007 to 2010, 2013 to 2014, and 2017 to 2020. Weighted univariate and multivariate logistic regression models were performed to explore the association between dietary zinc intake and osteoporosis or osteopenia in RA patients. The relationship was further investigated in different age, body mass index (BMI), nonsteroidal use, dyslipidemia, diabetes, and hypertension population. All results were presented as odds ratios (ORs) and confidence intervals (CIs). RESULTS: In total, 905 RA patients aged ≥ 40 years were included. After adjusting all covariates, higher dietary zinc intake was associated with lower odds of osteopenia or osteoporosis (OR = 0.39, 95%CI: 0.18-0.86) in RA patients. The relationship between dietary zinc intake ≥ 19.52 mg and lower odds of osteopenia or osteoporosis were also found in those aged ≥ 60 years (OR = 0.38, 95%CI: 0.16-0.91), BMI normal or underweight (OR = 0.16, 95%CI: 0.03-0.84), nonsteroidal use (OR = 0.14, 95%CI: 0.02-0.82), dyslipidemia (OR = 0.40, 95%CI: 0.17-0.92), diabetes (OR = 0.37, 95%CI: 0.14-0.95), and hypertension (OR = 0.37, 95%CI: 0.16-0.86). CONCLUSION: Higher dietary zinc intake was associated with reduced incidence of osteopenia or osteoporosis in patients with RA. Further longitudinal and randomized trials are necessary to validate our findings and explore the underling mechanisms. Adequate dietary zinc intake may beneficial to the bone health in RA patients.

Structural Properties and Surface Modification Decided Pharmacokinetic Behavior and Bio-Distribution of DNA Origami Frameworks in Mice.

This study establishes and validates a series of three dimentional (3D) DNA origami frameworks (DOFs) carrying imaging probes to evaluate their pharmacokinetics and real-time bio-distribution in mice. Three typical DOFs with distinguished structural properties are subjected to mice intravenous injection to systematically investigate their in vivo behaviors. Tracing the radioisotope zirconium-89 (89 Zr) trapped at the inner space of the frameworks, positron emission tomography (PET) imaging is employed to record the real-time bio-distribution of the structures and acquire their pharmacokinetic parameters in the major metabolic organs. The 3D DOFs show different behavior compared to previous structures, with lower kidney accumulation and higher liver retention. Modifications to the structures, such as exposed ssDNA or polyethylene glycol (PEG) moieties, impact their behavior, but are structure-dependent. The 43 nm icosahedra framework among the DOFs perform the best in liver targeting, with the ssDNA extensions enhancing this tendency. The modification of triantennary N-acetylgalactosamine (GalNAc), further improves its uptake in liver cells, especially in hepatocytes over other cell types, discovered by flow cytometry analysis.

[177Lu]Lu-PSMA-617 theranostic probe for hepatocellular carcinoma imaging and therapy.

PURPOSE: This study aimed to explore the feasibility of using [177Lu]Lu-prostate-specific membrane antigen (PSMA)-617 and [177Lu]Lu-Evans blue (EB)-PSMA-617 for in vivo radioligand therapy by single-dose administration in a PSMA-positive hepatocellular carcinoma (HCC) xenograft mouse model. METHODS: [177Lu]Lu-PSMA-617 and [177Lu]Lu-EB-PSMA-617 were prepared, and labelling efficiency and radiochemical purity were determined. A HepG2 human HCC subcutaneous xenograft mouse model was established. After intravenous injection of [177Lu]Lu-PSMA-617 or [177Lu]Lu-EB-PSMA-617 (37 MBq) into the mouse model, single-photon emission computed tomography/computed tomography (SPECT/CT) was performed. Biodistribution studies were conducted to verify targeting specificity and pharmacokinetics. In the radioligand therapy study, mice were randomized into 4 groups: 37 MBq [177Lu]Lu-PSMA-617, 18.5 MBq [177Lu]Lu-PSMA-617, 7.4 MBq [177Lu]Lu-EB-PSMA-617, and saline (control). A single-dose administration was applied at the beginning of therapy studies. Tumor volume, body weight, and survival were monitored every 2 days. After the end of therapy, mice were euthanized. Tumors were then weighed, and systemic toxicity was evaluated via blood testing and histological examination of healthy organs. RESULTS: [177Lu]Lu-PSMA-617 and [177Lu]Lu-EB-PSMA-617 were successfully prepared with high purity and stability. SPECT/CT and biodistribution showed that tumor uptake was higher and persisted longer for [177Lu]Lu-EB-PSMA-617 compared with [177Lu]Lu-PSMA-617. [177Lu]Lu-PSMA-617 was rapidly cleared from the blood, while [177Lu]Lu-EB-PSMA-617 persisted for significantly longer. In radioligand therapy studies, tumor growth was significantly suppressed in the 37 MBq [177Lu]Lu-PSMA-617, 18.5 MBq [177Lu]Lu-PSMA-617, and 7.4 MBq [177Lu]Lu-EB-PSMA-617 groups compared to the saline group. Median survival was 40, 44, 43, and 30 days, respectively. No healthy organ toxicity was observed in safety and tolerability evaluation. CONCLUSIONS: Radioligand therapy using [177Lu]Lu-PSMA-617 and [177Lu]Lu-EB-PSMA-617 significantly suppressed tumor growth and prolonged survival time in PSMA-positive HCC xenograft mice without obvious toxicity. These radioligands appear promising for clinical use in humans, and future studies are warranted.

Chlorin e6-loaded goat milk-derived extracellular vesicles for Cerenkov luminescence-induced photodynamic therapy.

PURPOSE: Photodynamic therapy (PDT) is a promising cancer treatment strategy with rapid progress in preclinical and clinical settings. However, the limitations in penetration of external light and precise delivery of photosensitizers hamper its clinical translation. As such, the internal light source such as Cerenkov luminescence (CL) from decaying radioisotopes offers new opportunities. Herein, we show that goat milk-derived extracellular vesicles (GEV) can act as a carrier to deliver photosensitizer Chlorin e6 (Ce6) and tumor-avid 18F-FDG can activate CL-induced PDT for precision cancer theranostics. METHODS: GEV was isolated via differential ultracentrifugation of commercial goat milk and photosensitizer Ce6 was loaded by co-incubation to obtain Ce6@GEV. Tumor uptake of Ce6@GEV was examined using confocal microscopy and flow cytometry. To demonstrate the ability of 18F-FDG to activate photodynamic effects against cancer cells, apoptosis rates were measured using flow cytometry, and the production of 1O2 was measured by reactive oxygen species (ROS) monitoring kit. Moreover, we used the IVIS device to detect Cherenkov radiation and Cerenkov radiation energy transfer (CRET). For animal experiments, a small-animal IVIS imaging system was used to visualize the accumulation of the GEV drug delivery system in tumors. PET/CT and CL images of the tumor site were performed at 0.5, 1, and 2 h. For in vivo antitumor therapy, changes of tumor volume, survival time, and body weight in six groups of tumor-bearing mice were monitored. Furthermore, the blood sample and organs of interest (heart, liver, spleen, lungs, kidneys, and tumor) were collected for hematological analysis, immunohistochemistry, and H&E staining. RESULTS: Confocal microscopy of 4T1 cells incubated with Ce6@GEV for 4 h revealed strong red fluorescence signals in the cytoplasm, which demonstrated that Ce6 loaded in GEV could be efficiently delivered into tumor cells. When Ce6@GEV and 18F-FDG co-existed incubated with 4T1 cells, the cell viability plummeted from more than 88.02 ± 1.30% to 23.79 ± 1.59%, indicating excellent CL-induced PDT effects. In vivo fluorescence images showed a peak tumor/liver ratio of 1.36 ± 0.09 at 24 h after Ce6@GEV injection. For in vivo antitumor therapy, Ce6@GEV + 18F-FDG group had the best tumor inhibition rate (58.02%) compared with the other groups, with the longest survival rate (35 days, 40%). During the whole treatment process, neither blood biochemical analysis nor histological observation revealed vital organ damage, suggesting the biosafety of this treatment strategy. CONCLUSIONS: The simultaneous accumulation of 18F-FDG and Ce6 in tumor tissues is expected to overcome the deficiency of traditional PDT. This strategy has the potential to extend PDT to a variety of tumors, including metastases, using targeted radiotracers to provide internal excitation of light-responsive therapeutics. We expect that our method will play a critical role in precision treatment of deep solid tumors.

Effects of high pressure on the lattice structure and electrical transport properties of BiOI.

To reveal the pressure effects on BiOX semiconductors, we performed in-situ Raman spectroscopy and electrical transport measurements on BiOI up to 26.1 GPa and 19.2 GPa. BiOI showed good structural stability, while the electron conduction characteristics maintained dominance throughout the pressure range. The influence of grain boundary conduction disappeared at pressures above 9.2 GPa. With pressure elevation, the pressure-induced lattice fragmentation and grain refinement introduced a large number of relevant levels in the energy gap and resulted in a significant increase in the conductivity of BiOI under compression. The conductivity increased by 106 at 19.2 GPa from the initial value and maintained an increase of 102 after depressurization until ambient conditions were attained. At the same time, the space charge polarization of the crystal interface layer became weaker with pressure elevation resulting in a decrease in the relative permittivity of BiOI. The calculation results of the complex permittivity showed that the frequency of orientation polarization response decreases with pressure elevation, and the complex permittivity becomes constant in the high-frequency region. Our work proves that pressure could significantly increase the carrier concentration and mobility, thus effectively improving the conductivity of BiOX semiconductors.

A candidate nanoparticle vaccine comprised of multiple epitopes of the African swine fever virus elicits a robust immune response.

The African swine fever (ASF) pandemics pose a significant threat to the global swine industry, and the development of safe and effective vaccines is a daunting but necessary challenge. The level and persistence of immunity are very important for the effectiveness of the vaccine. Targeting antigens to antigen presenting cells (APCs) can greatly enhance immunogenicity. In this study, we developed a self-assembled nano-ASFV vaccine candidate (NanoFVax) targeting DCs, by covalently coupling the self-assembled 24-mer ferritin with the dominant B and T cell epitopes of the highly immunogenic ASFV antigen (p72, CD2v, pB602L and p30) and fused with the chemokine receptor XCL1 (a DC targeting molecule) through the SpyTag/SpyCatcher protein ligase system. Compared to monomeric protein, the nanoparticle vaccines can induce a more robust T-cell response, and the high-level antibody response against ASFV can last for more than 231 days. Therefore, the NanoFVax is a novel and promising vaccine candidate for ASFV.

Customizing cancer treatment at the nanoscale: a focus on anaplastic thyroid cancer therapy.

Anaplastic thyroid cancer (ATC) is a rare but highly aggressive kind of thyroid cancer. Various therapeutic methods have been considered for the treatment of ATC, but its prognosis remains poor. With the advent of the nanomedicine era, the use of nanotechnology has been introduced in the treatment of various cancers and has shown great potential and broad prospects in ATC treatment. The current review meticulously describes and summarizes the research progress of various nanomedicine-based therapeutic methods of ATC, including chemotherapy, differentiation therapy, radioiodine therapy, gene therapy, targeted therapy, photothermal therapy, and combination therapy. Furthermore, potential future challenges and opportunities for the currently developed nanomedicines for ATC treatment are discussed. As far as we know, there are few reviews focusing on the nanomedicine of ATC therapy, and it is believed that this review will generate widespread interest from researchers in a variety of fields to further expedite preclinical research and clinical translation of ATC nanomedicines.

Berberin sustained-release nanoparticles were enriched in infarcted rat myocardium and resolved inflammation.

Inflammatory regulation induced by macrophage polarization is essential for cardiac repair after myocardial infarction (MI). Berberin (BBR) is an isoquinoline tetrasystemic alkaloid extracted from plants. This study analyzes the most likely mechanism of BBR in MI treatment determined via network pharmacology, showing that BBR acts mainly through inflammatory responses. Because platelets (PLTs) can be enriched in the infarcted myocardium, PLT membrane-coated polylactic-co-glycolic acid (PLGA) nanoparticles (BBR@PLGA@PLT NPs) are used, which show enrichment in the infarcted myocardium to deliver BBR sustainably. Compared with PLGA nanoparticles, BBR@PLGA@PLT NPs are more enriched in the infarcted myocardium and exhibit less uptake in the liver. On day three after MI, BBR@PLGA@PLT NPs administration significantly increases the number of repaired macrophages and decreases the number of inflammatory macrophages and apoptotic cells in infarcted rat myocardium. On the 28th day after MI, the BBR@PLGA@PLT group exhibits a protective effect on cardiac function, reduced cardiac collagen deposition, improved scar tissue stiffness, and an excellent angiogenesis effect. In addition, BBR@PLGA@PLT group has no significant impact on major organs either histologically or enzymologically. In summary, the therapeutic effect of BBR@PLGA@PLT NPs on MI is presented in detail from the perspective of the resolution of inflammation, and a new solution for MI treatment is proposed.

Nanomedicine for renal cell carcinoma: imaging, treatment and beyond.

The kidney is a vital organ responsible for maintaining homeostasis in the human body. However, renal cell carcinoma (RCC) is a common malignancy of the urinary system and represents a serious threat to human health. Although the overall survival of RCC has improved substantially with the development of cancer diagnosis and management, there are various reasons for treatment failure. Firstly, without any readily available biomarkers, timely diagnosis has been greatly hampered. Secondly, the imaging appearance also varies greatly, and its early detection often remains difficult. Thirdly, chemotherapy has been validated as unavailable for treating renal cancer in the clinic due to its intrinsic drug resistance. Concomitant with the progress of nanotechnological methods in pharmaceuticals, the management of kidney cancer has undergone a transformation in the recent decade. Nanotechnology has shown many advantages over widely used traditional methods, leading to broad biomedical applications ranging from drug delivery, prevention, diagnosis to treatment. This review focuses on nanotechnologies in RCC management and further discusses their biomedical translation with the aim of identifying the most promising nanomedicines for clinical needs. As our understanding of nanotechnologies continues to grow, more opportunities to improve the management of renal cancer are expected to emerge.

BRD4 inhibition exerts anti-viral activity through DNA damage-dependent innate immune responses.

Chromatin dynamics regulated by epigenetic modification is crucial in genome stability and gene expression. Various epigenetic mechanisms have been identified in the pathogenesis of human diseases. Here, we examined the effects of ten epigenetic agents on pseudorabies virus (PRV) infection by using GFP-reporter assays. Inhibitors of bromodomain protein 4 (BRD4), which receives much more attention in cancer than viral infection, was found to exhibit substantial anti-viral activity against PRV as well as a range of DNA and RNA viruses. We further demonstrated that BRD4 inhibition boosted a robust innate immune response. BRD4 inhibition also de-compacted chromatin structure and induced the DNA damage response, thereby triggering the activation of cGAS-mediated innate immunity and increasing host resistance to viral infection both in vitro and in vivo. Mechanistically, the inhibitory effect of BRD4 inhibition on viral infection was mainly attributed to the attenuation of viral attachment. Our findings reveal a unique mechanism through which BRD4 inhibition restrains viral infection and points to its potent therapeutic value for viral infectious diseases.

Advances in aptamer-based nuclear imaging.

Aptamers are short oligonucleotides that bind to specific target molecules. They have been extensively explored in biomedical applications, including biosensing, medical imaging, and disease treatment. Their adjustable affinity for specific biomarkers stimulates more translational efforts, such as nuclear imaging of tumors in preclinical and clinical settings. In this review, we present recent advances of aptamer-based nuclear imaging and compare aptamer tracers with other biogenic probes in forms of peptides, nanobodies, monoclonal antibodies, and antibody fragments. Fundamental properties of aptamer-based radiotracers are highlighted and potential directions to improve aptamer's imaging performance are discussed. Despite many translational obstacles to overcome, we envision aptamers to be a versatile tool for cancer nuclear imaging in the near future.

PET imaging of hepatocellular carcinoma by targeting tumor-associated endothelium using [68Ga]Ga-PSMA-617.

OBJECTIVE: Hepatocellular carcinoma (HCC) is a malignant tumor associated with high morbidity and mortality rates. In many non-prostate solid tumors such as HCC, prostate-specific membrane antigens (PSMA) are overexpressed in tumor-associated endothelial cells. Therefore, the aim of this study was to evaluate the performance of [68Ga]Ga-PSMA-617 PET imaging on HCC with different animal models, including cell line-derived xenografts (CDX) and patient-derived xenografts (PDX), and to explore its mechanisms of function. METHODS: [68Ga]Ga-PSMA-617 was prepared. The expression level of PSMA in two human hepatocellular cancer cells (HepG2 and HuH-7) was evaluated, and the cellular uptakes of [68Ga]Ga-PSMA-617 were assayed. HepG2 and HuH-7 subcutaneous xenograft models, HepG2 orthotopic xenograft models, and four different groups of PDX models were prepared. Preclinical pharmacokinetics and performance of [68Ga]Ga-PSMA-617 were evaluated in different types of HCC xenografts models using small animal PET and biodistribution studies. RESULTS: Low PSMA expression level of HepG2 and HuH-7 cells was observed, and the cellular uptake and blocking study confirmed the non-specificity of the PSMA-targeted probe binding to HepG2 and HuH-7 cells. In the subcutaneous xenograft models, the tumor uptakes at 0.5 h were 0.76 ± 0.12%ID/g (HepG2 tumors) and 0.78 ± 0.08%ID/g (HuH-7 tumors), respectively, which were significantly higher than those of the blocking groups (0.23 ± 0.04%ID/g and 0.20 ± 0.04%ID/g, respectively). In the orthotopic xenograft models, PET images clearly displayed the tumor locations based on the preferential accumulation of [68Ga]Ga-PSMA-617 in tumor tissue versus normal liver tissue, suggesting the possibility of using [68Ga]Ga-PSMA-617 PET imaging to detect primary HCC lesions in deep tissue. In the four different groups of HCC PDX models, PET imaging with [68Ga]Ga-PSMA-617 provided clear tumor uptakes with prominent tumor-to-background contrast, further demonstrating its potential for the clinical imaging of PSMA-positive HCC lesions. The staining of tumor tissue sections with CD31- and PSMA-specific antibodies visualized the tumor-associated blood vessels and PSMA expression on endothelial cells in subcutaneous, orthotopic tissues, and PDX tissues, confirming the imaging with [68Ga]Ga-PSMA-617 might be mediated by targeting tumor associated endothelium. CONCLUSION: In this study, in vivo PET on different types of HCC xenograft models illustrated high uptake within tumors, which confirmed that [68Ga]Ga-PSMA-617 PET may be a promising imaging modality for HCC by targeting tumor associated endothelium.

Multi-antitumor therapy and synchronous imaging monitoring based on exosome.

BACKGROUND: Tumor-derived exosomes (TEX) have shown great potential for drug delivery and tumor targeting. Here, we developed a novel multi-drug loaded exosomes nanoprobe for combined antitumor chemotherapy and photodynamic therapy, and monitoring the drug delivery capabilities with pre-targeting technique. METHODS: TEX of human colorectal cancer HCT116 was prepared, and Doxorubicin and the photodynamic therapy agent 5-aminolevulinic acid (ALA) were loaded and named as TEX@DOX@ALA. Tumor uptake was first examined using fluorescence imaging of the fluorescent dye Cy5 (TEX@DOX@ALA@Cy5). Visualization of exosome aggregation in tumor were realized by positron-emission tomography/computed tomography (PET/CT) with pre-targeting technique. Tumor-bearing mice were first injected with TEX@DOX@ALA labeled with azide (N3) (TEX@DOX@ALA@N3), and then 68Ga-(2,2'-((6-amino-1-(4,7-bis (carboxymethyl)-1,4,7-triazonan-1-yl) hexan-2-yl) azanediyl) diacetic acid-dibenzocyclooctyne (68Ga-L-NETA-DBCO) was injected after 24 h for PET/CT imaging via in vivo click chemistry. For the antitumor therapy with photodynamic and/or chemotherapy, seven groups of tumor-bearing mice with different therapy were monitored, and the tumor size, animal weight and the survival time were recorded. Furthermore, the samples of blood and interested tissues (heart, lung, liver, kidney, and spleen) were harvested for hematological analysis and H&E staining. RESULTS: The drug loading process did not influence the structure or the function of the HCT116 TEX membranes. In a fluorescence imaging experiment, higher fluorescence could be seen in tumor after TEX@DOX@ALA@Cy5 injected, and reached the highest signal at 24 h. From PET/CT images with subcutaneous and orthotopic colon tumor-bearing mice, clear radioactivity could be seen in tumors, which suggested the successes of TEX accumulation in tumors. TEX@DOX@ALA group with photodynamic therapy and chemotherapy had the best tumor inhibition effect compared with the other groups, with the longest survival time (36 days, 37.5%). No significant damage was found on histological observation and the blood biochemical analysis, which suggested the safety of the multi-drug loaded exosomes. CONCLUSIONS: We successfully engineered an exosome-based nanoprobe integrating PET imaging components and therapeutic drugs. This drug-loaded exosome system may effectively target tumors and enable synergistic chemotherapeutic and photodynamic antitumor effects.