Multifunctional drug delivery systems combining two or more therapies have a wide-range of potential for high efficacy tumor treatment. Herein, we designed a novel hollow mesoporous Prussian blue nanoparticles (HMPBs)-based platform for targeted and synergetic chemo-photothermal treatment of acute myeloid leukemia (AML). The HMPBs were first loaded with the anticancer drugs daunorubicin (DNR) and cytarabine (AraC), and were subsequently coated with polyethylenimine (PEI) through electrostatic adsorption. Then, zwitterionic sulfobetaine (ZS) and CXCR4 antagonist peptide E5 were modified onto the surface of the nanoparticles via covalent bonding to fabricate a nanoplatform (denoted as HMPBs(DNR + AraC)@PEI-ZS-E5). The nanoplatform showed excellent photothermal effects, superior photothermal stability, reduced nonspecific protein adsorption, efficient targeting capability, a constant hydrodynamic diameter and good biocompatibility. Additionally, a laser-responsive drug release pattern was observed. In vitro results indicated that the nanoplatform could achieve active targeting and remarkable chemo-photothermal synergetic therapeutic effects, showcasing its great potential in AML treatment.

Tumor photodynamic therapy (PDT) relies on intratumoral free radicals, while the limited oxygen source and the depletion of tissue oxygen may exacerbate the hypoxia. As the treatment progresses, there will eventually be a problem of insufficient free radicals. Here, it is found that Au@CeO2 nano-rods (Au@Ce NRs), assembled by gold nano-rods (Au NRs) and ceria nanoparticles (CeO2 NPs), can efficaciouslyabsorb near-infrared light (NIR) to promote the release of oxygen and free radicals. Au@Ce NRs exhibit a higher proportion of Ce3+ (Ce2O3) after oxygen release, while Ce3+ is subsequently oxidized to Ce4+ (CeO2) by trace H2O2. Interestingly, Au@Ce NRs re-oxidized by trace H2O2 can re-releasing oxygen and free radicals again upon NIR treatment, achieving oxygenation/oxygen evolution, similar to charging/discharging. This loop maximizes the conversion of limited oxygen source into highly cytotoxic free radicals. As a result, when B16-F10 cells are treated by NIR/Au@Ce NRs, more tumor cells undergo apoptosis, consistent with the higher level of free radicals. Importantly, NIR/Au@Ce NRs successfully suppresses tumor growth and promotes the generation of epidermal collagen fibers in the transplanted tumor model. Therefore, the rod-shaped Au@Ce NRs provide an ideal platform for maximizing the utilization of intratumoral oxygen sources and improving the treatment of melanoma. © 2024 Wiley‐VCH GmbH.

Ceria nanoparticles (CeO2NPs) exhibit great potential in cardiovascular disease and nonalcoholic fatty liver disease due to its excellent antioxidant capacity. However, the profitable effect of CeO2NPs on many diseases is almost all attributed to the regulation of ROS. Apart from the general antioxidant function, there seems to be no more distinct mechanism to reflect its unique multi-disease improvement effect. Here, we for the first time reveal a new discovery of CeO2NPs in mimicking nitric oxide synthase (NOS) by catalyzing L-arginine (L-Arg) to produce nitric oxide (NO) or the derivatives. NOS-like activity of CeO2NPs is original and associated with multiple factors like substrate concentration, pH, temperature and time, etc. where oxygen vacancy ratio plays a more critical role. Meanwhile, NOS-like activity of CeO2NPs successfully elevates NO secretion in endothelial cells and macrophages without expanding eNOS/iNOS expression. Importantly, NOS-like activity of CeO2NPs and the responsive endogenous NO promote the re-distribution of blood lipids and stabilize eNOS expression but suppress iNOS, thus collectively alleviate the accumulation of vascular plaque. Altogether, we provide a new angle of view to survey the outstanding potential of CeO2NPs, apart from the inevitable antioxidant capacity, the covert but possible and more critical NOS-like enzymatic activity is more noteworthy. © 2023. The Author(s).

Advanced ovarian cancer (OC) patients have limited benefit from current relevant cytotoxic and targeted therapies following debulking surgery. Therefore, new therapeutic strategies are in urgent need. Immunotherapy has shown great potential in tumor treatment, especially in tumor vaccine development. The study objective was to evaluate the immune effects of cancer stem cells (CSCs) vaccines on OC. The CD44+CD117+CSCs were isolated from human OC HO8910 and SKOV3 cells using the magnetic cell sorting system; the cancer stem-like cells were selected from murine OC ID8 cell by no-serum formed sphere culture. The CSC vaccines were prepared by freezing and thawing these CSCs, which were then injected into mice followed by challenging the different OC cells. The in vivo antitumor efficacy of CSC immunization revealed the vaccines were capable of significantly provoking immune responses to autologous tumor antigens in vaccinated mice as the mice were found to have markedly inhibited tumor growth, prolonged survival, and decreased CSC counts in OC tissues when compared to mice without the CSC vaccination. The in vitro cytotoxicities of immunocytes toward SKOV3, HO8910 and ID8 cells indicated a significant killing efficacy compared with the controls. However, the antitumor efficacy was remarkably reduced whilst the mucin-1 expression in CSC vaccines was down-regulated by small interfering RNA. Overall, findings from this study provided the evidence that has deepened our understanding of CSC vaccine immunogenicity and anti-OC efficacy, particularly for the role of dominant antigen mucin-1. It is possible to turn the CSC vaccine into an immunotherapeutic approach against ovarian cancer.

Glioblastoma (GBM) is the most invasive brain tumor and remains lack of effective treatment. The existence of blood-brain tumor barrier (BBTB) constitutes the greatest barrier to non-invasive delivery of therapeutic agents to tumors in the brain. Here, we propose a novel approach to specifically modulate BBTB and deliver magnetic hyperthermia in a systemic delivery mode for the treatment of GBM. BBTB modulation is achieved by targeted delivering fingolimod to brain tumor region via dual redox responsive PCL-SeSe-PEG (poly (Ε-caprolactone)-diselenium-poly (ethylene glycol)) polymeric nanocarrier. As an antagonist of sphingosine 1-phosphate receptor-1 (S1P1), fingolimod potently inhibits the barrier function of BBB by blocking the binding of sphingosine 1-phosphate (S1P) to S1P1 in endothelial cells. We found that the modulated BBTB showed slight expression level of tight junction proteins, allowing efficient accumulation of zinc- and cobalt- doped iron oxide nanoclusters (ZnCoFe NCs) with enhanced magnetothermal conversion efficiency into tumor tissues through the paracellular pathway. As a result, the co-delivery of heat shock protein 70 inhibitor VER-155008 with ZnCoFe NCs could realize synergistic magnetic hyperthermia effects upon exposure to an alternating current magnetic field (ACMF) in both GL261 and U87 brain tumor models. This modulation approach brings new ideas for the treatment of central nervous system diseases that require delivery of therapeutic agents across the blood-brain barrier (BBB). © 2023 Elsevier B.V.

无论是人类还是动物界,都面临着病原微生物的威胁,其中主要以细菌和病毒的危害性较大。及时准确的检测对于科学防控病原传播具有极其重要的意义。作为目前实验室最常用的核酸检测技术,聚合酶链式反应（polymerase chain reaction,PCR）已广泛应用于病原微生物的检测。然而,PCR方法要么依赖存在染料使用安全风险的琼脂糖凝胶电泳,要么需使用成本较高的荧光定量设备及配套试剂,且不适于现场即时检测（point-of-care testing,POCT）。近年来发展起来的等温扩增技术突破传统核酸体外扩增的固有限制,弥补了PCR方法在POCT应用方面的短板,但现有方法在引物设计、目标序列及灵敏度等方面仍有局限性,距离广泛应用仍有差距。此外,作为核酸检测的重要步骤,不同类型样本的DNA常规提取方法缺乏通用性,步骤冗繁,且提取的DNA质量也有待提高。针对上述问题,本研究在核酸提取与纯化、常规PCR、等温扩增等方面进行了试剂改良与方法创新。同时,针对不同应用条件下DNA/RNA检测需求,基于荧光免疫层析分别建立定量方法并应用于病原微生物的检测。主要工作如下:（1）基于磁珠的通用型DNA提取及纯化方法的建立。本研究通过优化实验,优选硅羟基磁珠为DNA提取磁珠。在CTAB法裂解液中加入40μL SDS溶液（15%,w/v）进行试剂改良。优选异丙醇为结合液,磁珠优选用量为40μL（30 mg/m L）,最后使用65℃进行洗脱。经实验验证,本研究方法可从多种类型的样本中高效、优质提取基因组DNA。接着,为了对PCR产物进行纯化,避免引物二聚体等对PCR定量产生干扰,建立了一种基于磁珠的核酸纯化方法。通过实验探索确定吸附液体积、PEG-8000工作浓度及Na Cl浓度对不同长度DNA片段的纯化作用,并通过肠炎沙门氏菌PCR产物进行了成功验证。（2）基于荧光免疫层析的PCR定量方法建立及在犬细小病毒2型检测中的应用。使用荧光微球作为荧光信号放大探针,提高了检测的灵敏度。运行缓冲液的优选工作体积为80μL、免疫层析检测时间为2 min。使用磁珠法对PCR产物进行纯化,有效解决了引物二聚体等导致的假阳性问题。该方法能特异性检测犬细小病毒2型,其cutoff值为146（荧光信号值）。检测灵敏度为30 copies/μL,比常规PCR高2个数量级。通过62份临床样品验证,检测结果与常规PCR一致。同时,通过对阳性样本VP2基因测序分析,确定病毒株的抗原类型。该方法操作安全、简单快速,检测结果可实现数字化定量。（3）基于荧光免疫层析的链交换等温扩增定量方法建立及在沙门氏菌检测中的应用。以重要食源性致病菌沙门氏菌为研究对象,通过对链交换等温扩增产物酶切和DNA测序验证了方法的准确性,并对扩增机制进行了分析。基于荧光免疫层析,核酸检测可在30 min内完成,其cutoff值为15,灵敏度为6 CFU/m L（纯培养物）或3×10~4 CFU/25 g（人工感染物）。特异性经89株沙门氏菌和15株非沙门氏菌参考株验证。对236份样品进行检测,结果与常规PCR一致。该方法简单、快速、灵敏且特异,适于病原微生物快速检测（POCT）。（4）基于荧光免疫层析的三引物增强链交换等温扩增定量方法建立及在新型冠状病毒检测中的应用。为提高对RNA的扩增效率以快速检测SARS-Co V-2,建立了一种三引物增强链交换等温扩增方法。通过酶切和DNA测序验证了方法的准确性,并对反应机制进行了分析。基于荧光免疫层析,可在1 h内实现定量检测。Rd RP和N基因扩增可在相同条件下进行,结果重复性好,灵敏度分别为90 copies/μL和70 copies/μL。本方法可特异性检测SARS-Co V-2,与其他临床症状相似的病毒和致病菌无交叉反应。模拟病毒感染物实验表明,Rd RP和N基因检测方法灵敏度分别为200 copies/m L和90 copies/m L,cutoff值分别为11和12。综上,基于磁珠的通用型DNA高效提取方法为核酸检测提供了高质量模板,PCR产物纯化方法为解决引物二聚体等干扰提供了方法支持。PCR定量方法为改进常规PCR提供了新的技术方案。链交换等温扩增方法弥补了现有方法在检测短序列靶标时的短板,且适于POCT应用。这两种定量方法可满足不同序列长度的核酸检测需求。三引物增强链交换等温扩增方法为高效检测RNA病原体提供了新的有力手段。本研究为实验室及POCT等不同应用条件下对不同类型的病原体进行核酸快速检测提供了针对性的解决方案。所建立的方法操作简单、安全、快速、灵敏、可数字化定量且适于推广使用,具有重要的实际应用价值。

Persistent inflammation within atherosclerotic plaquesis a crucialfactor contributing to plaque vulnerability and rupture. It has becomeincreasingly evident that the proinflammatory microenvironment ofthe plaque, characterized by heightened monocyte recruitment, oxidativestress, and impaired clearance of apoptotic cells, plays a significantrole in perpetuating inflammation and impeding its resolution. Consequently,targeting and eliminating these proinflammatory features within theplaque microenvironment have emerged as a promising therapeutic approachto restore inflammation resolution and mitigate the progression ofatherosclerosis. While recent advancements in nanotherapeutics havedemonstrated promising results in targeting individual proinflammatorycharacteristics, the development of an effective therapeutic strategycapable of simultaneously addressing multiple proinflammatory featuresremains a challenge. In this study, we developed a multifunctionalnanozyme based on Prussian blue, termed PBNZ@PP-Man, to simultaneouslytarget and eliminate various proinflammatory factors within the plaquemicroenvironment. Through systematic investigations, we have elucidatedthe antiatherosclerotic mechanisms of PBNZ@PP-Man. Our results demonstratethat PBNZ@PP-Man possesses the ability to accumulate within atheroscleroticplaques and effectively eliminate multiple proinflammatory factors,leading to inflammation resolution. Specifically, PBNZ@PP-Man suppressesmonocyte recruitment, scavenges reactive oxygen species, and enhancesefferocytosis. Notably, PBNZ@PP-Man exhibits a much stronger efficacyto resolve the proinflammatory plaque microenvironment and attenuateatherosclerosis in comparison to the approach that merely eliminatesone single risky factor in the plaque. It significantly enhances theinflammation resolution capabilities of macrophages and attenuatesatherosclerosis. These results collectively underscore the importanceof modulating the proinflammatory plaque microenvironment as a complementarystrategy for resolving inflammation in atherosclerosis.

Along with hypoxia, severe bacterial infection, and abnormal pH, continuous inflammatory response hinders diabetic wounds from healing. It leads to the accumulation of large amounts of reactive oxygen species (ROS) and therefore prevents the transition of diabetic wounds from the inflammatory phase to the proliferative phase. In this work, a nanohybrid double network hydrogel with injectable, self-healing, and tissue adhesion properties based on a platinum nanozyme composite (PFOB@PLGA@Pt) was constructed to manage diabetic wound healing. PFOB@PLGA@Pt exhibited oxygen supply capacity and enzyme catalytic performance accompanied by pH self-regulation in the entire phases of wound healing. In the first stage, the oxygen carried by perfluorooctyl bromide (PFOB) can ameliorate the hypoxia and boost the glucose oxidase-like catalyzed reaction of Pt NPs, leading to a lowered pH environment with gluconic acid. As a result, the NADH oxidase-like, peroxidase-like, and oxidase-like multiple enzyme activities were activated successively, leading to synergistic antibacterial effects through the production of ROS. After the bacterial infection had cleared, the catalase-like and superoxide dismutase-like activities of Pt NPs reshaped the redox microenvironment by scavenging the excess ROS, which transitioned the wound from the inflammatory phase to the proliferative phase. The microenvironmentally adaptive hydrogel treatment can cover all phases of wound healing, showing the significant promoting effect in the repair of diabetic infected wounds. © 2023 American Chemical Society

Currently, multimodal synergistic nanoplatform emerges as an important cancer therapy paradigm, however, multimodal synergistic theranostic nanoplatform remains to be developed. Herein, using the mouse model of breast cancer, a versatile multimodal synergistic theranostic nanoplatform is rationally designed and synthesized for enhancing chemodynamic therapy (CDT), overcoming immunosuppression within tumor microenvironment, and inhibiting metastasis as well as tracking tumor. To fulfill our design, a composite Fe/Mn magnetic nanoparticle is first synthesized by loading with Fe3O4 and BMS-202 (PD-L1 inhibitor) within a poly(lactide-co-glycolide)-based nanoparticle core, which are further modified with in situ synthesis of MnO2 layer. Then, the composite metal-organic nanoparticle is coated with two targeting moieties hyaluronic acid (HA) and AMD3100 (CXCR4 antagonist), respectively, to achieve the multimodal synergistic theranostic nanoplatform (FMN-BMS@HA+AMD). With surface targeting modification, FMN-BMS@HA+AMD exhibits enhanced tumor accumulation, where it effectively consumes endogenous glutathione to generate Mn2+ allowing for the enhanced CDT effect, alleviates tumor hypoxia by O2 generation and reverses the tumor immunosuppression. FMN-BMS@HA+AMD blocks CXCR4 receptor on cancer cells, thus suppressing the CXCR4-mediated cancer metastasis and invasion. Additionally, FMN-BMS@HA+AMD would synchronously be achieving tumor tracking by T1-T2 dual-mode magnetic resonance imaging. Collectively, this strategy holds a novel multimodal synergistic theranostics for effective cancer management. © 2022 Elsevier Ltd

As pioneering Fe3O4 nanozymes, their explicit peroxidase (POD)-like catalytic mechanism remains elusive. Although many studies have proposed surface Fe2+-induced Fenton-like reactions accounting for their POD-like activity, few have focused on the internal atomic changes and their contribution to the catalytic reaction. Here we report that Fe2+ within Fe3O4 can transfer electrons to the surface via the Fe2+-O-Fe3+ chain, regenerating the surface Fe2+ and enabling a sustained POD-like catalytic reaction. This process usually occurs with the outward migration of excess oxidized Fe3+ from the lattice, which is a rate-limiting step. After prolonged catalysis, Fe3O4 nanozymes suffer the phase transformation to gamma-Fe2O3 with depletable POD-like activity. This self-depleting characteristic of nanozymes with internal atoms involved in electron transfer and ion migration is well validated on lithium iron phosphate nanoparticles. We reveal a neglected issue concerning the necessity of considering both surface and internal atoms when designing, modulating, and applying nanozymes.The mechanism of peroxidase-like Fe3O4 nanozymes remains elusive. Here, the authors show the electron transfer mechanism of Fe(II) ions to regenerate surface Fe(II) and the related phase transformation and depletion of activity.