Drug Design Development and Therapy
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2024
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IF 4.7
Yong-Yu Yang,Rong-Rong Deng,Da-Xiong Xiang
Background Ferroptosis plays a crucial role in the occurrence and development of cerebral ischemia-reperfusion (I/R) injury and is regulated by mitogen-activated protein kinase 1/2 (ERK1/2). In China, Naodesheng Pills (NDSP) are prescribed to prevent and treat cerebrosclerosis and stroke. However, the protective effects and mechanism of action of NDSP against cerebral I/R-induced ferroptosis remain unclear. We investigated whether NDSP exerts its protective effects against I/R injury by regulating ferroptosis and aimed to elucidate the underlying mechanisms.Methods The efficacy of NDSP was evaluated using a Sprague-Dawley rat model of middle cerebral artery occlusion and an in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) model. Brain injury was assessed using 2,3,5-triphenyltetrazolium chloride (TTC), hematoxylin and eosin staining, Nissl staining, and neurological scoring. Western blotting was performed to determine the expression levels of glutathione peroxidase 4 (GPX4), divalent metal-ion transporter-1 (DMT1), solute carrier family 7 member 11 (SLC7A11), and transferrin receptor 1 (TFR1). Iron levels, oxidative stress, and mitochondrial morphology were also evaluated. Network pharmacology was used to assess the associated mechanisms.Results NDSP (1.08 g/kg) significantly improved cerebral infarct area, cerebral water content, neurological scores, and cerebral tissue damage. Furthermore, NDSP inhibited I/R- and OGD/R-induced ferroptosis, as evidenced by the increased protein expression of GPX4 and SLC7A11, suppression of TFR1 and DMT1, and an overall reduction in oxidative stress and Fe2+ levels. The protective effects of NDSP in vitro were abolished by the GPX4 inhibitor RSL3. Network pharmacology analysis revealed that ERK1/2 was the core target gene and that NDSP reduced the amount of phosphorylated ERK1/2.Conclusion NDSP exerts its protective effects against I/R by inhibiting cerebral I/R-induced ferroptosis, and this mechanism is associated with the regulation of ferroptosis via the ERK1/2 signaling pathway.
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CHEMICAL ENGINEERING JOURNAL
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2024
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IF 13.3
Xiaoning Yu,Haoqi Pan,Qing He,Jing Yang,Mingming Xiao,Jin Xu,Wei Wang,Xianjun Yu,Si Shi
The inhibitory immune microenvironment of pancreatic cancer prevents the infiltration and activation of antitumor immune cells. Therefore, breaking the barrier of pancreatic cancer immune microenvironment is the key to activate antitumor immunity, but there is still no effective method reported so far. Immunogenic cell death (ICD) of tumor cells is considered to be an effective method to activate antitumor immunity. Accordingly, we designed and synthesized a dual-gated nanodrug based on MXene, which can not only specifically target pancreatic cancer cells and induce ICD, but also effectively regulate the immune microenvironment. Tumor cells undergo ferroptosis, a typical kind of ICD, which allowed a large number of tumor-associated antigens (TAA) to be released from the cytoplasm into the microenvironment. Dendritic cells (DCs) were attracted and promoted maturation. Activated DCs processed and presented TAA to T cells, which was a necessary process for T cell activation and ultimately heated up the cold tumor immune microenvironment of pancreatic cancer. In general, our work is an interesting and important exploration, aiming to apply MXene nanoparticles with great potential to the treatment of pancreatic cancer, and provide new ideas and directions for the biomedical application of related materials.
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ACS Applied Nano Materials
·
2024
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IF 5.3
Fanqi Meng,Lei Chen,Haoran Chen,Meili Shen,Guangyi Wang,Yulei Chang
Combined phototherapy with other therapeutic strategies can improve the therapeutic outcomes of tumors and reduce the side effects. However, shaping multiple modalities for combination therapy remains challenging. Herein, multiple stimuli-responsive drug-loaded micelles are presented, which are self-assembled from cypate-conjugated pH-sensitive poly(ethylene glycol)–poly(2-(diisopropylamino) ethyl methacrylate)–poly(2-aminoethyl methacrylate hydrochloride) and redox-responsive poly(glycidyl methacrylate)–poly(propylene sulfide) copolymer and loaded with chemo agents doxorubicin (DOX) and sorafenib (SRF, also a ferroptosis inducer) for enhanced tumor therapy. The DOX and SRF chemo drugs were encapsulated into the hydrophobic core of PPS and PDPA to enable multiple stimuli-responsive controlled drug delivery. In vivo and in vitro experiments are carried out to investigate the potential application for controlled drug release and systemic chemo-phototherapy. This study highlights the rational design of cypate-based drug-loaded micelles, offering multiple stimuli-responsive drug releases and synergistic photo-, ferro-, and chemotherapy in colorectal cancer.
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Acta Biomaterialia
·
2024
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IF 9.4
Dihai Gu,Lin Zhu,Zhaohan Wang,Xu Zhi,Min Liu,Shuwang Ge,Baiwang Sun,Xiao Liang,Hongshuai Wu,Yihong Wang
Ferroptosis is greatly restricted by low reactive oxygen species (ROS) generation efficiency, and the inherent self-protection mechanism originating in heat shock proteins (HSPs) seriously impedes the efficiency of photothermal therapy (PTT). Herein, we designed an intelligent strategy utilizing cascade catalytic nanoassemblies (Au@COF@MnO 2 ) with triple-enzyme activity for amplifying ferroptosis therapy and improving the efficiency of PTT in tumor. Gold nanozyme was encapsulated within a hollow manganese dioxide (MnO 2 ) shell with the help of covalent organic frameworks (COFs). The nanoassemblies possess the ability of photothermal conversion. Mechanism studies suggested that glutathione (GSH) depletion by Au@COF@MnO 2 leads to the inactivation of glutathione peroxidase 4 (GPX4). This effect synergized with Mn 2+ -mediated reactive oxygen species (ROS) generation to enhance the accumulation of lipid peroxide (LPO), thereby inducing high-efficiency ferroptosis. Notably, gold nanozyme facilitated the conversion of glucose into gluconic acid and hydrogen peroxide (H 2 O 2 ). This process augmented the endogenous H 2 O 2 levels necessary for Fenton chemistry, which could effectively promote the generation of ROS. Simultaneously, glucose depletion downregulated the expression of HSPs induced by hyperthermia, consequently reducing cellular heat resistance for enhancing PTT. Therefore, the cascade catalytic nanoassembly not only exhibits high tumor inhibition and admirable biosafety, but also possesses trimodal imaging performance for imaging-guided tumor therapy in vivo, holding great potential for clinical application. Statement of Significance This study engineered multi-responsive cascade catalytic nanoassembly (Au@COF@MnO 2 ) with triple enzymatic functions for amplifying ferroptosis therapy and improving the efficiency of PTT in tumor. The nanoassembly exhibited multi-responsive release and great photothermal conversion performance. Glucose consumption-evoked starvation downregulated the hyperthermia-induced expression of HSPs in tumor cells, thereby improving the efficacy of PTT. Mechanism studies suggested that GSH depletion by Au@COF@MnO 2 lead to the inactivation of GPX4, which synergized with Mn 2+ -mediated ROS generation to bolster the accumulation of LPO, thereby inducing high-efficiency ferroptosis. Moreover, the nanoassembly demonstrated trimodal (PT, PA, and MR) imaging in vivo, enabling the visualization of the tumor treatment with nanoassembly. Such nanoassembly exhibited high tumor inhibition and admirable biosafety in tumor therapy in vivo, holding a great potential for clinical application.
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Journal of Functional Biomaterials
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2024
·Vol. 15
·期 8
·205
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IF 5
Zihan Zhuo,Chunfang Yin,Zhenqing Zhang,Yumeng Han,Haoye Teng,Qi Xu,Changming Li
The issue of bacterial resistance is an escalating problem due to the misuse of antibiotics worldwide. This study introduces a new antibacterial mechanism, the ferroptosis-like death (FLD) of bacteria, and an approach to creating green antibacterial nano-reactors. This innovative method leverages natural iron-containing ovotransferrin (OVT) assembled into an organic skeleton to encapsulate low-concentration adriamycin (ADM) for synthesizing eco-friendly nano-reactors. FLD utilizes the Fenton reaction of reactive oxygen species and ferrous ions to continuously produce ·OH, which can attack the bacterial cell membrane and destroy the cell structure to achieve bacteriostasis. The OVT@ADM nano-reactors are nearly spherical, with an average diameter of 247.23 nm and uniform particle sizing. Vitro simulations showed that Fe3+in OVT@ADM was reduced to Fe2+by glutathione in the bacterial periplasmic space, which made the structure of OVT loose, leading to a sustained slow release of ADM from OVT@ADM. The H2O2continuously produced by ADM oxidized Fe2+through the Fenton reaction to produce ·OH and Fe3+. The results of the antibacterial assay showed that OVT@ADM had a satisfactory antibacterial effect againstS. aureus, and the inhibition rate was as high as 99.3%. The cytotoxicity results showed that the mitigation strategy significantly reduced the cytotoxicity caused by ADM. Based on the FLD mechanism, OVT@ADM nano-reactors were evaluated and applied to bacteriostasis. Therefore, the novel antibacterial mechanism and OVT@ADM by the green synthesis method have good application prospects.
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ACS Applied Materials & Interfaces
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2025
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IF 8.2
Li Yang,Wei-Hua Zhang,Yan Li,Yan-Li An,Ye-Ming Wu,Ning Gu,Gao-Jun Teng
Noninvasive therapies such as photodynamic therapy (PDT) and chemodynamic therapy (CDT), which rely on reactive oxygen species (ROS), are gaining attention for their low toxicity. However, single-modal treatments have individual limitations that restrict the therapeutic efficacy. Fe(III) can coordinate with the hydrophilic regions of indocyanine green (ICG) molecules to form the ICG/Fe(III) complex, making it a promising dual-modal agent for combined PDT and CDT. However, coordination with Fe(III) leads to the aggregation quenching of ICG, hindering its application in dual-modal therapy. We innovatively utilize oxygen nanobubbles, prepared solely from water and oxygen, to significantly reverse the aggregation-induced quenching of the ICG/Fe(III) complex, thereby enhancing its stability in aqueous environments. In this system, Fe(III) assembles at the nanobubble interface, coordinating with ICG’s hydrophilic regions to form the ICG/Fe(III)-NBs. The oxygen nanobubbles boost PDT efficiency by improving the ICG/Fe(III) complex stability and oxygen content, while Fe(III) achieves CDT by generating hydroxyl radicals (•OH) through the Fenton reaction. This dual-modality treatment significantly disrupts the tumor’s redox balance, induces ferroptosis, and demonstrates strong antitumor efficacy, reducing tumor volume to 34% of its initial size in mice. The strategy offers a promising and clinically viable approach to cancer treatment.
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Nano Today
·
2024
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IF 13.2
Chenghui Liu,Mingzhu Lv,Qiqi Xu,Jiani Xie,Yong You,Kun Guo,Guohui Jiang,Lingmi Hou,Hanfeng Yang,Yuan Yong
Chronic wounds are a serious complication for diabetic patients, causing substantial inconvenience and significant economic burden to patients, due to their characteristics of sequential development encountering bacterial infections, excessive reactive oxygen species (ROS)-induced inflammation and M1 macrophage accumulation. Herein, we developed a chronological adaptive Fe-based polyoxometalate on hyaluronic acid (Fe-POM@HA) hydrogel for diabetic chronic wounds, whose capacity can be strengthened by synergistic the acid-activated and glutathione-enhanced NIR-II photothermal therapy and achieving spatiotemporal selective and adaptive inhibition of bacterial infection. During the bacteria-infection slightly acidic stage, Fe-POM catalyzes endogenous H 2 O 2 for ROS generation inducing bacterial ferroptosis, suppressing glutathione peroxidase activity, and promoting lipid peroxidation to disrupt the bacterial biofilm. As the wound transitions to neutral inflammation stage, Fe-POM with Fe 2+ /Mo 5+ mixed valences can simultaneously alleviate oxidative stress and overcome the hypoxia microenvironment by continuously scavenging excessive ROS for endogenous H 2 O 2 cyclic accumulation and O 2 sustainable replenishment. Importantly, the Fe-POM@HA hydrogel could further promote wound angiogenesis at the new tissue proliferation stage through the immunomodulation of macrophage polarization and inflammatory factor expression. Therefore, Fe-POM@HA hydrogel provides a promising chronologically adaptive protocol for the repair and regeneration of chronic cutaneous wounds addressing complex clinical demands.
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International Journal of Nanomedicine
·
2024
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IF 6.6
Minghui Li,Jiabi Wu,Tao Yang,Yuhang Zhao,Ping Ren,Lingling Chang,Pilong Shi,Jing Yang,Yuhang Liu,Xiaolei Li,Peng Wang,Yonggang Cao
Background Cardiac microvascular damage is substantially related with the onset of myocardial ischaemia-reperfusion (IR) injury. Reportedly, allicin (AL) effectively protects the cardiac microvascular system from IR injury. However, the unsatisfactory therapeutic efficacy of current drugs and insufficient drug delivery to the damaged heart are major concerns. Here, inspired by the natural interaction between neutrophils and inflamed cardiac microvascular endothelial cells (CMECs), a neutrophil membrane-camouflaged nanoparticle for non-invasive active-targeting therapy for IR injury by improving drug delivery to the injured heart is constructed.Methods In this study, we engineered mesoporous silica nanoparticles (MSNs) coated with a neutrophil membrane to act as a drug delivery system, encapsulating AL. The potential of the nanoparticles (named AL@MSNs@NM) for specific targeting of infarcted myocardium was assessed using small animal vivo imaging system. The cardiac function of AL@MSNs@NM after treatment was evaluated by Animal Ultrasound Imaging system, HE staining, and Laser Speckle Imaging System. The therapeutic mechanism was analyzed by ELISA kits, immunofluorescence, and PCR.Results We discovered that AL@MSNs@NM significantly improves cardiac function index, reduced infarct size and fibrosis, increased vascular perfusion in ischemic areas, and also promoted the function of CMECs, including migration, tube formation, shear stress adaptation, and nitric oxide production. Further research revealed that AL@MSNs@NM have cardio-protective functions in IR rats by inhibiting CMEC ferroptosis and increasing platelet endothelial cell adhesion molecule-1 (PECAM-1) expression.Conclusion Our results indicated that AL@MSNs@NM significantly reversed CMEC ferroptosis and increased PECAM-1 expression, enhanced cardiac function, and reduced myocardial infarction size. Therefore, this strategy demonstrates that engineered biomimetic nanotechnology effectively delivers AL for targeted therapy of myocardial infarction.
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COLLOIDS AND SURFACES B-BIOINTERFACES
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2025
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IF 5.6
Qianqian Zhao,Ting Wu,Chunming Tang,Jie Li,Min Wu,Jie Wu,Zhiji Wang,Yinxin Zhu,Huae Xu,Xiaolin Li
Combination chemotherapy is considered more effective than monotherapy in enhancing clinical outcomes. Ferroptosis, a unique form of regulated cell death, has been demonstrated to inhibit tumor growth and progression. Consequently, combining ferroptosis with chemotherapy represents a promising and innovative approach to antitumor therapy. In this study, we developed a novel TMTP1-modified biomimetic nanocrystal (TRNC@P + L) for the co-delivery of PTX and LF3, aiming to achieve ferroptosis-combined chemotherapy in gastric cancer. TRNC@P + L, which incorporates a tumor-homing peptide-modified red blood cell membrane, demonstrated efficient tumor targeting, prolonged circulation, enhanced drug bioavailability, and reduced non-specific toxicities of free PTX and LF3. By utilizing the synergistic effects of PTX and LF3, TRNC@P + L combination therapy significantly inhibited tumor growth, as demonstrated by both in vitro and in vivo studies. Mechanistically, TRNC@P + L triggers ferroptosis in tumor cells by downregulating GPX4 expression, the promotion of ROS accumulation, and the enhancement of lipid peroxidation. These processes synergistically enhance the anticancer efficacy of PTX.
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CHEMICAL ENGINEERING JOURNAL
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2024
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IF 13.3
Yanxuan Xiao,Caiyong Song,Hongping Ye,Dan Li,Jiayi Shi,Xiaoke Huang,Qianming Chen,Rui Liu
Radiation-induced oral mucositis (RIOM) is a common complication among patients undergoing radiotherapy. Ionizing radiation (IR) has been shown to induce the excessive production of reactive oxygen species (ROS) and ferroptosis, both of which play critical roles in the development of RIOM. This study fabricates a novel detachable dissolvable microneedle patch DC@MNs for the therapy of RIOM. The nano-enzyme Ceria nanoparticles (Ceria NPs) at the top of needle tips can scavenge ROS and enhance penetration capability of DC@MNs. Additionally, the microneedles (MNs) incorporate deferoxamine (DFO), a known ferroptosis inhibitor, to form a combined therapeutic strategy for RIOM. Cell viability assays demonstrate that the combination of DFO and Ceria NPs effectively mitigates IR-induced cell death. Furthermore, in vivo studies using rat RIOM models further confirm that DC@MNs can penetrate the mucosal epithelium, thereby facilitating drug delivery. Finally, measurement of intracellular ROS, lipid peroxidation, and ferrous ion levels reveals that the DC@MNs protect oral mucosal cell through ROS scavenging and ferroptosis inhibition. This study provides a novel radiation protection strategy and highlights its potential applicability in drug delivery to oral mucosal for patients receiving radiotherapy.
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BIOMATERIALS
·
2024
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IF 12.8
Mengyao Chen,Xiaohan Tong,Yanting Sun,Chunyan Dong,Chen Li,Chunhui Wang,Minyi Zhang,Yixuan Wen,Pinting Ye,Ruihao Li,Jie Wan,Shujing Liang,Shuo Shi
As an iron dependent regulatory cell death process driven by excessive lipid peroxides (LPO), ferroptosis is recognized as a powerful weapon for pancreatic cancer (PC) therapy. However, the tumor microenvironment (TME) with hypoxia and elevated glutathione (GSH) expression not only inhibits LPO production, but also induces glutathione peroxidase 4 (GPX4) mediated LPO clearance, which greatly compromise the therapeutic outcomes of ferroptosis. To address these issues, herein, a novel triple-enhanced ferroptosis amplifier (denoted as Zal@HM-PTBC) is rationally designed. After intravenous injection, the overexpressed H 2 O 2 /GSH in TME induces the collapse of Zal@HM-PTBC and triggers the production of oxygen and reactive oxygen species (ROS), which synergistically amplify the degree of lipid peroxidation (broaden sources). Concurrently, GSH consumption because of the degradation of the hollow manganese dioxide (HM) significantly weakens the activity of GPX4, resulting in a decrease in LPO clearance (reduce expenditure). Moreover, the loading and site-directed release of zalcitabine further promotes autophagy-dependent LPO accumulation (enhance effectiveness). Both in vitro and in vivo results validated that the ferroptosis amplifier demonstrated superior specificity and favorable therapeutic responses. Overall, this triple-enhanced LPO accumulation strategy demonstrates the ability to facilitate the efficacy of ferroptosis, injecting vigorous vitality into the treatment of PC.
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Advanced Healthcare Materials
·
2025
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IF 9.6
Lu Liu,Daiyong Chao,Qing Dong,Xianli Zhang,Kai Zhang,Zhenyu Ju
Doxorubicin (DOX), a potent anthracycline chemotherapeutic agent, is widely used in cancer treatment but is associated with significant adverse effects, particularly DOX-induced cardiomyopathy (DIC). DIC pathogenesis involves the generation of reactive oxygen species (ROS) and ferroptosis induction. Novel therapeutic strategies targeting antioxidant defenses and ferroptosis inhibition are essential for mitigating DIC. An innovative bimetallic metal-organic framework (MOF), NiCu-MOF (NCM), is developed, exhibiting multifaceted antioxidant enzyme-mimicking activities that effectively scavenge a broad spectrum of ROS. Additionally, the bimetallic NCM exhibits excellent iron-chelating ability. In vitro experiments demonstrate that NCM significantly reduces cardiomyocyte death by attenuating ROS levels and inhibiting ferroptosis. Furthermore, in a mouse model of DIC, NCM treatment results in substantial myocardial protection, evidenced by improved cardiac function and structural integrity. This protective effect is attributed to suppression of ferroptosis, preservation of mitochondrial function, and attenuation of inflammatory responses. Collectively, these findings highlight biocompatible NCM's potential as a novel cardioprotective agent and offer a promising therapeutic strategy for managing DIC.
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