Potentiating dual-directional immunometabolic regulation with nanomedicine to enhance anti-tumor immunotherapy following incomplete photothermal ablation.

Photothermal therapy (PTT) is a promising cancer treatment method due to its ability to induce tumor-specific T cell responses and enhance therapeutic outcomes. However, incomplete PTT can leave residual tumors that often lead to new metastases and decreased patient survival in clinical scenarios. This is primarily due to the release of ATP, a damage-associated molecular pattern that quickly transforms into the immunosuppressive metabolite adenosine by CD39, prevalent in the tumor microenvironment, thus promoting tumor immune evasion. This study presents a photothermal nanomedicine fabricated by electrostatic adsorption among the Fe-doped polydiaminopyridine (Fe-PDAP), indocyanine green (ICG), and CD39 inhibitor sodium polyoxotungstate (POM-1). The constructed Fe-PDAP@ICG@POM-1 (FIP) can induce tumor PTT and immunogenic cell death when exposed to a near-infrared laser. Significantly, it can inhibit the ATP-adenosine pathway by dual-directional immunometabolic regulation, resulting in increased ATP levels and decreased adenosine synthesis, which ultimately reverses the immunosuppressive microenvironment and increases the susceptibility of immune checkpoint blockade (aPD-1) therapy. With the aid of aPD-1, the dual-directional immunometabolic regulation strategy mediated by FIP can effectively suppress/eradicate primary and distant tumors and evoke long-term solid immunological memory. This study presents an immunometabolic control strategy to offer a salvage option for treating residual tumors following incomplete PTT.

Biomimetic nanoprobe-augmented triple therapy with photothermal, sonodynamic and checkpoint blockade inhibits tumor growth and metastasis.

BACKGROUND: Comprehensive antitumor therapy through integrated multimodal means has drawn increasing attention owing to its high efficiency and metastasis suppression. RESULTS: We describe a synergistic triple protocol combining photothermal and sonodynamic therapy (PTT and SDT), together with immune checkpoint blockade for the inhibition of breast cancer growth and metastases in the 4T1 mouse model. PTT and SDT are synergistically augmented by a novel multimodal imaging nanoprobe integrated with cancer cell membrane-biomimetic nanoparticles (CHINPs) loaded with superparamagnetic iron oxide (SPIO) and hematoporphyrin monomethyl ether (HMME). CHINPs exhibit excellent homologous tumor targeting, and are sequentially triggered by ultrasound and near infrared (NIR) light under the guidance of magnetic resonance, photoacoustic and photothermal imaging, leading to complete in situ tumor eradication and systemic anti-tumor immune activation. Further combination of this approach with immune checkpoint blockade therapy is shown to suppress tumor metastasis. CONCLUSION: This work provides proof-of-principle for triple therapy using multimodal imaging-guided PTT/SDT based on biomimetic nanoprobes in combination with immunotherapy to eliminate tumors.

NIR-responsive nanoplatform for pre/intraoperative image-guided carcinoma surgery and photothermal ablation of residual tumor tissue.

Local recurrence is common among patients with advanced cancer who have undergone surgery. Here, we developed a new surgical treatment for cancer based on a nanoparticle that loaded a near-infrared dye (IR780 iodide) and perfluorooctyl bromide into liposomes (NP-IR780). In an orthotopic breast cancer mouse model, NP-IR780 was demonstrated to have excellent tumor-targeting ability due to the selective tumor accumulation of IR780 iodide and the enhanced permeation and retention effect of the nanoparticle. With the excellent targeting ability, concurrent computed tomography and photoacoustic imaging were achieved for preoperative planning. In particular, NP-IR780 could serve as a tumor indicator for near-infrared fluorescence image-guided precise resection of lesions during surgery. Importantly, residual tumors could be ablated through intraoperative photothermal therapy without obvious recurrence. This work provides a theranostic strategy that significantly improved the survival of mice through pre/intraoperative image-guided tumor resection and subsequent photothermal therapy of residual lesions.

[Prevalence of symptomatic orthostatic hypotension and orthostatic blood pressure changes].

OBJECTIVE: To analyze the prevalence and orthostatic blood pressure changes in subjects with symptomatic orthostatic hypotension (OH), and to observe the relation between symptoms and orthostatic blood pressure change in this population. METHODS: A total of 193 subjects who consulted physicians due to OH related symptoms were selected, and divided into three groups: young (n = 37), middle-aged (n = 66) and elder (n = 90). Height, body weight, waist circumference, hip circumference and resting heart rate were measured. Symptom scores of every subject were obtained. CAVI and ABI were measured. Blood pressure including recumbent position, orthostatic systolic and diastolic blood pressure was measured at the morning and at the afternoon on two separate examination days with at least one week interval. After that, orthostatic changes in systolic blood pressure (OCs) and orthostatic changes in diastolic blood pressure (OCd) were calculated. RESULTS: OH prevalence was 32.6% in this cohort. The prevalence of three groups was similar [young: 32.4%, middle-aged: 25.8%, and elderly: 37.8%, respectively (P > 0.05)]. Only 9 cases (14.29% of confirmed OH cases) reached the OH diagnostic criteria with equal or more than 2 times orthostatic blood pressure measurements. OH was diagnosed in 63 patients during the 4 times orthostatic blood pressure check, of which 19.5% to 57.14% cases were diagnosed with single orthostatic blood pressure check. Age, weight, body mass index, waist-to-hip ratio, smoking, drinking habit, sex, coronary heart disease, hypertension, Parkinson's disease, stroke history, antihypertensive drug use were similar between OH group and non-OH group. Height, waist circumference, hip circumference, and resting heart rate were significantly lower in OH group than in non-OH group (P < 0.05). The values of the factors in OH group were lower. CAVI was 8.45 ± 0.19 in non-OH group and 8.37 ± 0.27 in OH group (P > 0.05), ABI was significantly lower in OH group than in non-OH group (1.004 ± 0.013 vs. 1.051 ± 0.009, P < 0.01). CONCLUSION: The prevalence of OH in people with related symptoms is high. Repeated orthostatic blood pressure measurements can improve OH detection rate.

Thiol-yne click post-synthesis of phenylboronic acid-functionalized magnetic cyclodextrin microporous organic network for selective and efficient extraction of antiepileptic drugs.

Owing to their incomplete digestion in the human body and inadequate removal by sewage treatment plants, antiepileptic drugs (AEDs) accumulate in water bodies, potentially affecting the exposed humans and aquatic organisms. Therefore, sensitive and reliable detection methods must be urgently developed for monitoring trace AEDs in environmental water samples. Herein, a novel phenylboronic acid-functionalized magnetic cyclodextrin microporous organic network (Fe3O4@CD-MON-PBA) was designed and synthesized via the thiol-yne click post-modification strategy for selective and efficient magnetic solid-phase extraction (MSPE) of trace AEDs from complex sample matrices through the specific B-N coordination, π-π, hydrogen bonding, electrostatic, and host-guest interactions. Fe3O4@CD-MON-PBA exhibited a large surface area (118.5 m2 g-1), rapid magnetic responsiveness (38.6 emu g-1, 15 s), good stability and reusability (at least 8 times), and abundant binding sites for AEDs. Under optimal extraction conditions, the proposed Fe3O4@CD-MON-PBA-MSPE-HPLC-UV method exhibited a wide linear range (0.5-1000 µg L-1), low limits of detection (0.1-0.5 µg L-1) and quantitation (0.3-2 µg L-1), good anti-interference ability, and large enrichment factors (92.2-104.3 to 92.3-98.0) for four typical AEDs. This work confirmed the feasibility of the thiol-yne click post-synthesis strategy for constructing novel and efficient multifunctional magnetic CD-MONs for sample pretreatment and elucidated the significance of B-N coordination between PBA and N-containing AEDs.

[Characteristics and Risk Assessment of Antibiotic Contamination in Oujiang River Basin in Southern Zhejiang Province].

Antibiotic pollution in the environment has a negative impact on ecosystem security. Taking the Oujiang River Basin as an example,high-performance liquid chromatography mass spectrometry(LC-MS)was used to detect the concentration of six classes of 35 antibiotics in the surface water of the southern Zhejiang River Basin. The concentration level and spatial distribution of antibiotics were analyzed,the risk of antibiotics to ecology and human health were assessed using relevant models,and the sources of antibiotics were discussed. The results showed that in 20 sampling sites,a total of four classes of 12 antibiotics were detected,including sulfonamides,quinolones,tetracyclines,and lincosamides. The total concentration was ND-1 018 ng·L-1. The highest detection rate was that of Lincomycin(90.48%),followed by that of sulfapyridine(38.10%). The three antibiotics with the highest average concentrations were ofloxacin(12.49 ng·L-1),Lincomycin(11.08 ng·L-1),and difloxacin(7.38 ng·L-1). Antibiotics in the basin showed mainly spotty pollution,which had large spatial differentiation. The average concentration of antibiotics in the upstream(54.39 ng·L-1)was higher than that mid-downstream(46.64 ng·L-1). The degree of antibiotic pollution from upstream to downstream showed a characteristic of being "sparse in the upstream and dense in the downstream. " This indicated that the concentration of antibiotics in the upstream was significantly different,whereas the pollution degree of antibiotics in the downstream was uniform. The upstream was mainly polluted by health,livestock,and poultry breeding wastewater emissions,and downstream pollution was mainly caused by densely populated activities and the rapid development of economy,trade,and industry. The ecological risk assessment results showed that the upstream site H6 had the highest risk quotient,ofloxacin and enrofloxacin had high risk levels, and lincomycin had a moderate risk level. Health risk assessment results showed that the Oujiang River surface water antibiotics posed no risk to human health.

A Collaborative Learning Model for Skin Lesion Segmentation and Classification.

The automatic segmentation and classification of skin lesions are two essential tasks in computer-aided skin cancer diagnosis. Segmentation aims to detect the location and boundary of the skin lesion area, while classification is used to evaluate the type of skin lesion. The location and contour information of lesions provided by segmentation is essential for the classification of skin lesions, while the skin disease classification helps generate target localization maps to assist the segmentation task. Although the segmentation and classification are studied independently in most cases, we find meaningful information can be explored using the correlation of dermatological segmentation and classification tasks, especially when the sample data are insufficient. In this paper, we propose a collaborative learning deep convolutional neural networks (CL-DCNN) model based on the teacher-student learning method for dermatological segmentation and classification. To generate high-quality pseudo-labels, we provide a self-training method. The segmentation network is selectively retrained through classification network screening pseudo-labels. Specially, we obtain high-quality pseudo-labels for the segmentation network by providing a reliability measure method. We also employ class activation maps to improve the location ability of the segmentation network. Furthermore, we provide the lesion contour information by using the lesion segmentation masks to improve the recognition ability of the classification network. Experiments are carried on the ISIC 2017 and ISIC Archive datasets. The CL-DCNN model achieved a Jaccard of 79.1% on the skin lesion segmentation task and an average AUC of 93.7% on the skin disease classification task, which is superior to the advanced skin lesion segmentation methods and classification methods.

Preparation and characterization of high embedding efficiency epigallocatechin-3-gallate glycosylated nanocomposites.

Glycosylated protein nano encapsulation was an efficient encapsulation technology, but its embedding rate for EGCG was not high, and the research on the embedding mechanism was relatively weak. Based on this, this study compared the embedding effect of glycosylated peanut globulin and glycosylated casein on EGCG. The embedding mechanism of EGCG with glycosylated protein was discussed by ultraviolet, fluorescence, infrared and fluorescence microscopy. Results revealed that the highest encapsulation efficiency of EGCG was 93.89 ± 1.11%. The neutral pH value and 0.3 mg/mL EGCG addition amount were suitable for EGCG glycosylated nanocomposites. The hydrogen bond between EGCG hydroxyl group and tyrosine and tryptophan of glycosylated protein is mainly non covalent. The encapsulation effect of EGCG glycosylated nanocomposites could be quenched by changing the polar environment and spatial structure of the group. The fluorescence characteristic and dispersibility of EGCG glycosylated peanut globin were higher than EGCG glycosylated casein. This study might provide a theoretical basis for EGCG microencapsulation technology and EGCG application in tea beverage and liquid tea food systems.

Stability of glycosylated complexes loaded with Epigallocatechin 3-gallate (EGCG).

The application of Epigallocatechin-3-gallate (EGCG) in food industry was limited by its low stability in aqueous solutions and poor bioavailability in vivo. The novel EGCG glycosylated arachin nanoparticles (Ara-CMCS-EGCG) and EGCG glycosylated casein nanoparticles (Cas-CMCS-EGCG) were prepared to improve the stability and bioavailability of EGCG. The effect of different variables on the storage stability and the slow-release behavior of novel glycosylation complexes in nanoparticle background solution and artificial gastrointestinal fluid were investigated. The results showed that the DPPH scavenging activity of Ara-CMCS-EGCG and Cas-CMCS-EGCG were stable in temperature (25 âˆ¼ 70 °C). EGCG could enhance the crosslinking effect of molecular particles in glycosylation complexes solution. The glycosylated protein nanoparticles were stable to acid-base and enzymolysis in simulated gastrointestinal fluid. The release rate of EGCG in simulated intestinal fluid was higher than that in simulated gastric fluid. The glycosylated protein carrier can not only release EGCG slowly, but also significantly improve the stability and bioavailability of EGCG in simulated gastrointestinal fluid.

Magnetic Response Combined with Bioactive Ion Therapy: A RONS-Scavenging Theranostic Nanoplatform for Thrombolysis and Renal Ischemia-Reperfusion Injury.

Currently, the limited efficacy of antithrombotic treatments is attributed to the inadequacy of pure drugs and the low ability of drugs to target the thrombus site. More importantly, timely thrombolysis is essential to reduce the sequelae of cardiovascular disease, but ischemia-reperfusion injury (IRI) remains a major challenge that must be solved after blood flow recovery. Herein, a multifunctional therapeutic nanoparticle (NP) based on Fe3O4 and strontium ions encapsulated in mesoporous polydopamine was successfully constructed and then loaded with TNK-tPA (FeM@Sr-TNK NPs). The NPs (59.9 min) significantly prolonged the half-life of thrombolytic drugs, which was 3.04 times that of TNK (19.7 min), and they had good biological safety. The NPs were shown to pass through vascular models with different inner diameters, curvatures, and stenosis under magnetic targeting and to enable accurate diagnosis of thrombi by photoacoustic imaging. NPs combined with the magnetic hyperthermia technique were used to accelerate thrombolysis and quickly open blocked blood vessels. Then, renal IRI-induced functional metabolic disorder and tissue damage were evidently attenuated by scavenging toxic reactive oxygen and nitrogen species and through the protective effects of bioactive ion therapy, including reduced apoptosis, increased angiogenesis, and inhibited fibrosis. In brief, we constructed a multifunctional nanoplatform for integrating a "diagnosis-therapy-protection" approach to achieve comprehensive management from thrombus to renal IRI, promoting the advancement of related technologies.

[Impact of attack frequency and therapy strategies on outcome of patients with vasovagal syncope].

OBJECTIVE: To analyze the impact of attack frequency as well as therapy strategies on outcome of patients with vasovagal syncope (VVS). METHODS: A total of 159 patients (aged from 15 - 59 years old) with VVS were included in this study. Patients were divided into low frequency (< 3) group (n = 95) and high (≥ 3) frequency group (n = 64) according to the attack frequency in the past 5 years at the primary survey. Patients received one of the three therapies: no treatment, physical therapy, and comprehensive treatment. All cases were followed up with telephone or outpatient visit for 24 months. RESULTS: Incidence of syncope was significantly higher in the high frequency group and in the low frequency group [40.6% (26/64) vs. 11.6% (11/95), P < 0.01]. The overall improvement rate was significantly higher in the low frequency group than that of high frequency group (P < 0.01). Improvement rate was significantly higher in the physical therapy subgroup and the comprehensive treatment subgroup than no treatment subgroup for patients with low attack frequency [81.8% (27/33) vs. 47.1% (8/17), P < 0.05; 82.2% (37/45) vs. 47.1% (8/17), P < 0.05], and in comprehensive treatment subgroup than in physical therapy subgroups observed between and [62.2% (28/45) vs. 31.6% (6/19), P < 0.05] for patients with high attack frequency. CONCLUSION: Outcome is related to previous attack frequency for patients with VVS, physical therapy is effective for reducing the recurrence rate of syncope in VVS patients with low attack frequency while physical therapy combined with pharmacotherapy should be applied for VVS patients with high attack frequency to improve outcome.

Mitochondrial Glutathione Depletion Nanoshuttles for Oxygen-Irrelevant Free Radicals Generation: A Cascaded Hierarchical Targeting and Theranostic Strategy Against Hypoxic Tumor.

An oxygen-irrelevant free radicals generation strategy has shown great potential in hypoxic tumor therapy. However, insufficient tumor accumulation, nonspecific intracellular localization, and the presence of highly reductive mitochondrial glutathione (GSH) dramatically hamper the free radicals therapeutic efficacy. Herein, a hierarchical targeting system was constructed by Fe-doped polydiaminopyridine nanoshuttles, indocyanine green (ICG), and an oxygen-irrelevant radicals generator (AIPH) to possess a negative charge. An acid-specific charge-reverse capability of the shuttles was achieved to enhance cell uptake in the tumor microenvironment (TME). In addition, the iron release occurs only in the acidic TME, which can be used as acidity enhancers to strengthen the charge-reverse process, thereby leading to more efficient tumor internalization and deep penetration. Moreover, such a nanosystem has significantly improved the delivery efficiency of nanoshuttles (16.06%) in the tumor tissues at 24 h postinjection, much higher than that of naked Fe-doped polydiaminopyridine (6.59%). More importantly, the nanoshuttles enable simultaneously mitochondria targeting and corresponding GSH depleting capability to show advantages in free radicals-based therapy after charge reversion, leading to a powerful tumor inhibition rate (>95%). The prescence of iron could allow for magnetic resonance imaging, while ICG allowed for photoacoustic imaging and fluorescence imaging to guide the therapeutic process. The remarkable features of the nanoshuttles may open a new avenue to explore an oxygen-irrelevant free radicals generating system for accurate cancer theranostics.

Impact of Inoculating with Indigenous Bacillus marcorestinctum YC-1 on Quality and Microbial Communities of Yibin Yacai (Fermented Mustard) during the Fermentation Process.

Bacillus species play an important role in improving the quality of some fermented foods and are also one of the dominant bacteria in Yibin Yacai (fermented mustard). However, little is known about their effects on the quality of Yibin Yacai. Here, the effect of Bacillus marcorestinctum YC-1 on the quality and microbial communities of Yibin Yacai during the fermentation process was investigated. Results indicated that the inoculation of Bacillus marcorestinctum YC-1 promoted the growth of Weissella spp. and Lactobacillus spp. and inhibited the growth of pathogens, accelerating the synthesis of free amino acids and organic acids and the degradation of nitrite. Furthermore, inoculating Yibin Yacai with YC-1 could effectively enhance the synthesis of alcohols and terpenoids in yeasts, thus producing more linalool, terpinen-4-ol, and α-muurolen in Yibin Yacai, and endowing it with pleasant floral, fruity, woody, and spicy aromas. These findings reveal that the inoculation of B. marcorestinctum YC-1 can improve the quality and safety of Yibin Yacai by changing microbial communities as fermentation proceeds.

Magnet-Guided Bionic System with LIFU Responsiveness and Natural Thrombus Tropism for Enhanced Thrombus-Targeting Ability.

Background: Arterial thrombosis is a serious threat to human health. Recently, many thrombus-targeted nanoparticles (NPs) have been constructed for detecting thrombi or monitoring thrombolysis, but their thrombus-targeting performance is limited. Considering this drawback, we designed a specific bionic system with enhanced thrombus-targeting ability. Materials and Methods: In the bionic system, gelatin was chosen as a carrier, and Fe3O4 served as a magnetic navigation medium and a magnetic resonance (MR) imaging agent. The CREKA peptide, which targets fibrin, was conjugated to the surface of gelatin to prepare targeted NPs (TNPs), which were then engulfed by macrophages to construct the bionic system. At the targeted site, the bionic system released its interior TNPs under low-intensity focused ultrasound (LIFU) irradiation. Moreover, the targeting performance was further improved by the conjugated CREKA peptide. Results: In this study, we successfully constructed a bionic system and demonstrated its targeting ability in vitro and in vivo. The results indicated that most TNPs were released from macrophages under LIFU irradiation at 2 W/cm2 for 10 min in vitro. Additionally, the enhanced thrombus-targeting ability, based on the natural tropism of macrophages toward inflammatory thrombi, magnetic navigation and the CREKA peptide, was verified ex vivo and in vivo. Moreover, compared with the bionic system group, the group treated with TNPs had significantly decreased liver and spleen signals in MR images and significantly enhanced liver and spleen signals in fluorescence images, indicating that the bionic system is less likely to be cleared by the reticuloendothelial system (RES) than TNPs, which may promote the accumulation of the bionic system at the site of the thrombus. Conclusion: These results suggest that the magnet-guided bionic system with LIFU responsiveness is an excellent candidate for targeting thrombi and holds promise as an innovative drug delivery system for thrombolytic therapy.

A Fibrin Site-Specific Nanoprobe for Imaging Fibrin-Rich Thrombi and Preventing Thrombus Formation in Venous Vessels.

Venous thromboembolism (VTE) is a prevalent public health issue worldwide. Before treatment, spatiotemporally accurate thrombus detection is essential. However, with the currently available imaging technologies, this is challenging. Herein, the development of a novel fibrin-specific nanoprobe (NP) based on the conjugation of poly(lactic-co-glycolic acid) with the pentapeptide Cys-Arg-Glu-Lys-Ala (CREKA) for selective and semiquantitative imaging in vivo is presented. By integrating Fe3 O4 and NIR fluorochrome (IR780), the NP can function as a highly sensitive sensor for the direct analysis of thrombi in vivo. The fibrin-specific NP distinguishes fibrin-rich thrombi from collagen-rich or erythrocyte-rich thrombi, which can be beneficial for future individually tailored therapeutic strategy. Furthermore, loading NPs with the ketotifen fumarate results in mast cell degranulation inhibition, and hence, NPs can prevent thrombosis without the risk of excessive bleeding. Thus, the use of fibrin-specific NPs may serve as a safe alternative approach for the detection and prevention of VTEs in susceptible populations in the future.

LIFU-responsive nanomedicine enables acoustic droplet vaporization-induced apoptosis of macrophages for stabilizing vulnerable atherosclerotic plaques.

Due to the high risk of tearing and rupture, vulnerable atherosclerotic plaques would induce serious cardiovascular and cerebrovascular diseases. Despite the available clinical methods can evaluate the vulnerability of plaques and specifically treat vulnerable plaques before a cardiovascular event, but the efficiency is still low and undesirable. Herein, we rationally design and engineer the low-intensity focused ultrasound (LIFU)-responsive FPD@CD nanomedicine for the highly efficient treatment of vulnerable plaques by facilely loading phase transition agent perfluorohexane (PFH) into biocompatible PLGA-PEG-PLGA nanoparticles (PPP NPs) and then attaching dextran sulphate (DS) onto the surface of PPP NPs for targeting delivery. DS, as a typical macrophages-targeted molecule, can achieve the precise vaporization of NPs and subsequently controllable apoptosis of RAW 264.7 macrophages as induced by acoustic droplet vaporization (ADV) effect. In addition, the introduction of DiR and Fe3O4 endows nanomedicine with near-infrared fluorescence (NIRF) and magnetic resonance (MR) imaging capabilities. The engineered FPD@CD nanomedicine that uses macrophages as therapeutic targets achieve the conspicuous therapeutic effect of shrinking vulnerable plaques based on in vivo and in vitro evaluation outcomes. A reduction of 49.4% of vascular stenosis degree in gross pathology specimens were achieved throughout the treatment period. This specific, efficient and biosafe treatment modality potentiates the biomedical application in patients with cardiovascular and cerebrovascular diseases based on the relief of the plaque rupture concerns.

A theranostic metallodrug modulates immunovascular crosstalk to combat immunosuppressive liver cancer.

Hepatocellular carcinoma (HCC) is a highly malignant, fatal disease with a complex tumor microenvironment (TME) characterized by severe immunosuppression and malformed vascular structures, thus most advanced HCC patients do not respond well to current mainstream pharmacotherapy and T-cell-related immunotherapy. Therefore, an efficient immunovascular crosstalk modulation strategy may help combat HCC by reversing immunosuppression and vessel normalization, especially by reprogramming tumor associated macrophages (TAMs). In this study, tyrosine kinase inhibitor lenvatinib (Len) was loaded into mesoporous Fe3O4 (mFe) nanoparticles (NPs), and bovine serum albumin (BSA) was attached to the NP surface to produce a metallodrug (BSA-mFe@Len NPs). In acidic TME, BSA allowed pH-responsive Len release and mFe exposure. Len directly triggered HCC apoptosis and changed the abnormal TME via vessel normalization, cytotoxic T-lymphocyte recruitment, and regulatory T-cell elimination at tailored dosages. After TAM phagocytosis, mFe NPs reprogrammed TAMs into M1 phenotypes to synergistically amplify antitumor immunity. The metallodrug achieved significant tumor growth inhibition, induced tumor vessel normalization effects, and acquired instant antitumor immunity as well as long-term immune memory in vivo. Furthermore, it displayed good T2 weighted magnetic resonance imaging performance, indicating potential theranostic applications. Collectively, this research provides new insights for unleashing the multifaceted potential of current pharmaceuticals in synergy with metallic nanomedicine for treating intractable liver cancer. STATEMENT OF SIGNIFICANCE: Current pharmacotherapy and immunotherapy have limited success in treating advanced hepatocellular carcinoma (HCC) due to its complex tumor microenvironment (TME). Hence, this work first put forward a theranostic metallodrug by loading lenvatinib (Len) into mesoporous Fe3O4 (mFe) nanoparticles (NPs) and coating a pH-degradable bovine serum albumin corona onto the surface. The metallodrug was able to modulate immunovascular TME for combating HCC via metalloimmunotherapy induced by the mFe NPs and Len's multiple functions (direct triggering of tumor apoptosis, vessel normalization, cytotoxic T-lymphocyte recruitment, and regulatory T-cell elimination). In vivo experiments showed that the metallodrug could significantly inhibit HCC growth and evoke long-term antitumor immune memory, paving a new avenue for treating advanced HCC patients.

Combination Nanotherapeutics for Dry Eye Disease Treatment in a Rabbit Model.

PURPOSE: Anti-inflammation is essential for dry eye disease. Traditional anti-inflammation agent corticosteroids applied in dry eye disease (DED) treatment could result in high intraocular pressure, especially in long-term treatment. Thus, we have prepared a liposome loading 1-bromoheptadecafluorooctane and tetrandrine (PFOB@LIP-Tet) to treat DED via anti-inflammation that hardly affects intraocular pressure in this study, which provided another therapy strategy for dry eye disease. METHODS: We firstly detected the physicochemical properties of PFOB@LIP-Tet. Next, we tested the biosafety of synthesized liposomes for corneal epithelium. Then, we explored the accumulations and distribution of PFOB@LIP-Tet both in cellular and animal models. And then, we assessed the therapeutic effects of PFOB@LIP-Tet formulations by laboratory and clinical examinations. Last, we examined the changes in eye pressure before and after treatment. RESULTS: PFOB@LIP-Tet and Tet showed a characteristic absorption peak at 282 nm while PFOB@LIP did not. Large amounts of PFOB@LIP-Tet remained on the ocular surface and accumulated in the corneal epithelial cells in DED rabbits. Corneal staining scores of DED rabbits respectively treated by ATS, PFOB@LIP-ATS, Tet-ATS and PFOB@LIP-Tet-ATS for seven days were 3.7±0.5, 3.2±0.4, 1.5±0.5 and 0.5±0.5. The expressions of related cytokines were correspondingly downregulated significantly, indicating that the inflammation of DED was successfully suppressed. The intraocular pressure changes of DED rabbits before and after treatment by PFOB@LIP-Tet showed no statistical significance. CONCLUSION: We successfully synthesized PFOB@LIP-Tet, and it could effectively treat dry eye disease via anti-inflammation but hardly affected the intraocular pressure.

Multifunctional nanozyme for multimodal imaging-guided enhanced sonodynamic therapy by regulating the tumor microenvironment.

Sonodynamic therapy (SDT) is a highly promising approach for cancer therapy, but its efficacy is severely hampered by the low specificity of sonosensitizers and the unfavorable characteristics of the tumor microenvironment (TME), such as hypoxia and glutathione (GSH) overexpression. To solve these problems, in this work, we encapsulated IR780 and MnO2 in PLGA and linked Angiopep-2 (Ang) to synthesize a multifunctional nanozyme (Ang-IR780-MnO2-PLGA, AIMP) to enhance SDT. With Ang functionalization to facilitate blood-brain barrier (BBB) penetration and glioma targeting, and through the function of IR780, these nanoparticles (NPs) showed improved targeting of cancer cells, especially mitochondria, and spread deep into tumor centers. Upon low-intensity focused ultrasound (LIFU) irradiation, reactive oxygen species (ROS) were produced and induced tumor cell apoptosis. Combined with the specific mitochondria-targeting ability of IR780, the sonodynamic effects were amplified because mitochondria are sensitive to ROS. In addition, MnO2 exhibited enzyme-like activity, reacting with the high levels of hydrogen protons (H+), H2O2 and GSH in the TME to continuously produce oxygen and consume GSH, which further enhanced the effect of SDT. Moreover, Mn2+ can be released in response to TME stimulation and used as a magnetic resonance (MR) contrast agent. In addition, IR780 has photoacoustic (PA)/fluorescence (FL) imaging capabilities. Our results demonstrated that AIMP NPs subjected to LIFU triggering maximally enhanced the therapeutic effect of SDT by multiple mechanisms, including multiple targeting, deep penetration, oxygen supply in situ and GSH depletion, thereby significantly inhibiting tumor growth and distal metastasis without systemic toxicity. In summary, this multifunctional nanozyme provides a promising strategy for cancer diagnosis and treatment under the intelligent guidance of multimodal imaging (PA/FL/MR) and may be a safe clinical translational method.

Tumor-self-targeted "thermoferroptosis-sensitization" magnetic nanodroplets for multimodal imaging-guided tumor-specific therapy.

Ferroptosis-based nanomedicine has drawn increasing attention in antitumor therapy because of the advantages of this unconventional mode of apoptosis, but the difficulties of delivery to the tumor site and surface-to-core penetration after arrival seriously hinder further clinical transformation and application. Herein, we propose an unprecedented strategy of injecting magnetic nanodroplets (MNDs) to solve these two longstanding problems. MNDs are nanocarriers that can carry multifunctional drugs and imaging materials. MNDs can effectively accumulate in the tumor site by active tumor targeting (multifunctional drugs) and passive tumor targeting (enhanced permeability and retention effect), allowing diffusion of the MNDs from the surface to the core through mild-temperature magnetic fluid hyperthermia (MHT) under multimodal imaging guidance. Finally, the ferroptosis pathway is activated deep within the tumor site through the drug release. This approach was inspired by the ability of mild-temperature MHT to allow MNDs to quickly pass through the blood vessel-tumor barrier and deeply penetrate the tumor tissue from the surface to the core to amplify the antitumor efficacy of ferroptosis. This strategy is termed as "thermoferroptosis sensitization". Importantly, this behavior can be performed under the guidance of multimodal imaging, making the design of MNDs for cancer therapy safer and more reasonable.