JOURNAL OF NANOBIOTECHNOLOGY
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2025
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IF 12.6
Wei-Hua Zhang,Lei Chen,Lin Gao,Ye-Ming Wu,Zhi-Cheng Jin,Jian-Jian Chen,Yan-Li An,Gao-Jun Teng
Incomplete radiofrequency ablation (iRFA) often results in tumor recurrence and therapeutic resistance, presenting significant clinical challenges. Tumors subjected to sublethal thermal injury activate the HSP70/ NQO1 antioxidant pathway and secrete elevated levels of CCL2, which recruits macrophages and fosters an immunosuppressive tumor microenvironment. To address these issues, this study engineered copper-doped ZIF-8 nanoparticles that co-deliver the hypoxia-activated prodrug TH-302 and the NQO1-targeting quinone β-lapachone, encapsulated within genetically engineered M1 macrophage membranes overexpressing CCR2 (CCR2-M). This innovative CCR2-M biomimetic coating enhances tumor targeting by sequestering excess CCL2, effectively reducing pro-tumoral macrophage infiltration. β-lapachone selectively targets NQO1-overexpressing tumor cells, elevating intracellular H 2 O 2 levels, while copper-doped ZIF-8 catalyzes Fenton-like reactions to generate cytotoxic hydroxyl radicals. Simultaneously, TH-302, responsive to hypoxia, complements β-lapachone by inducing cell death in hypoxic regions, thereby mitigating β-lapachone’s oxygen dependence. This synergistic ROS burst effectively suppressing tumor growth, activating the cGAS-STING pathway and enhancing tumor antigen presentation. This synergistic ROS burst effectively suppresses tumor growth, activates the cGAS-STING pathway and enhances tumor antigen presentation. This cascade recruits dendritic cells and cytotoxic CD8 + T cells, ultimately reversing the immunosuppressive microenvironment induced by iRFA. No drug-related toxicity was observed. Thus, this rationally designed nanotherapeutic strategy significantly curtails residual tumor growth and offers a promising immunomodulatory approach to overcoming therapeutic resistance in cancer treatment after iRFA.
研究领域:
纳米医学
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癌症免疫治疗
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肿瘤微环境
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仿生纳米材料
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放射肿瘤学
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JOURNAL OF NANOBIOTECHNOLOGY
·
2026
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IF 15
Yu Jiang,Yaowu Zhang,Jingqi Hou,Heng Liu,Xianyu Dai,Yuchuan Hou
Characterizing the tumor immune microenvironment (TIME) to explore potential therapeutic targets is fundamental to advancing precision tumor immunotherapy. However, the immunosuppressive nature of “cold” tumors, notably prostate cancer, poses a significant barrier to immunotherapy, demanding new approaches to simultaneously reinvigorate anti-tumor immunity and modulate the molecular drivers of immune evasion. Here, we identified VSIG4 as a key regulator of prostate tumor-resident macrophage fate through single-cell sequencing analysis. Meanwhile, a shikonin (Shik)-mediated downregulation of VSIG4 in macrophages is verified, potentially attenuating its immunosuppressive effects. Building on these findings, cytosine guanine dinucleotide (CpG) oligodeoxynucleotide (ODN)-modified manganese (Mn)-Shik metal-polyphenol network nanodrugs (Mn/Shik@CpG NDs) are designed to reverse the “cold” immune environment of prostate tumor. In this scenario, Mn/Shik@CpG NDs release monomeric components under the stimulation of acidic and glutathione-rich tumor microenvironment (TME), thus exerting their immunomodulatory effects synergistically. Since the released Shik can induce DNA damage by necroptosis promoting reactive oxygen species production, cGAS-STING signaling pathway is initiated, which further activates interferon production in the TME. In addition, the necroptosis of Shik initiates immunogenic cell death, further activating innate immunity and promoting adaptive immune responses. Mn 2+ is a cGAS-STING sensitizer, which amplifies the intratumoral interferon response. As an immune adjuvant, CpG ODN effectively promotes the maturation of dendritic cells, as well as the helper T cell differentiation and pro-inflammatory cytokine secretion, thus activating both innate and adaptive immunity. In vivo studies suggest that Shik-mediated VSIG4 downregulation, combined with innate and adaptive immune activation, remodels the TIME to evoke a significant anti-tumor response. Furthermore, transcriptomic analysis of rechallenged tumors indicated this durable protection was driven by a genuine immune memory response, revealing a gene signature of T cell activation and immune reprogramming. Collectively, beyond presenting a novel therapeutic candidate for converting immunologically “cold” tumors into “hot” ones, our work validates a data-guided design pipeline, offering a conceptual blueprint to inform the precise engineering of future nanodrugs.
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Materials Today Bio
·
2026
·
IF 10.2
Henan Xu,Yuxin Jiang,Ruohao Zhang,Daguang Wang,Jing Feng,Hongjie Zhang
Chemotherapy and photothermal therapy (PTT) have made prominent progress in the treatment of gastric cancer. However, the poor targeting of chemotherapeutic drugs and the thermotolerance or collateral damage induced by PTT lead to suboptimal therapeutic outcomes. To address these issues, we developed a mild PTT (mPTT) nanoparticle based on mesoporous polydopamine (MPDA), loaded with oxaliplatin (OXP) and manganese dioxide (MnO 2 ), and coated with tumor cell membranes to enhance the targeting capability. On one hand, this nanoparticle disrupts glycolysis by inhibiting hypoxia-inducible factor (HIF), while suppressing heat shock proteins (HSP) to mitigate tumor "thermotolerance." On the other hand, the reactive oxygen species (ROS) generated by the MnO 2 -mediated Fenton-like reaction, OXP, and mPTT also induce immunogenic cell death (ICD) to boost adaptive immunity, as well as activate the cGAS-STING pathway through tumor DNA damage to reinforce innate immunity. The activation of both adaptive and innate immune responses triggers a potent antitumor immune reaction, which, combined with chemotherapy and enhanced mPTT, significantly suppresses tumor growth, metastasis and recurrence. This strategy not only enhances the targeting of chemotherapeutic drugs but also provides new possibilities for expanding the field of immunotherapy in gastric cancer by regulating tumor metabolism and enhancing mPTT.
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Asian Pacific Journal of Tropical Biomedicine
·
2026
·Vol. 16
·期 6
·225
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IF 1.9
Zhang Rui,Zhou Yang,Xiao Ting,Gu Yan
Objective: To evaluate the effect of isorhamnetin on diabetic kidney disease and elucidate its underlying mechanisms. Methods: A high glucose-stimulated mouse podocyte (MPC-5) model was employed to evaluate the effects of isorhamnetin on podocyte injury, secretion of inflammatory cytokines, NLRP3 inflammasome activation, pyroptosis, mitochondrial function, cytosolic release of mtDNA, and activation of the cGAS-STING signaling pathway. Nigericin (an NLRP3 activator) and siRNA were used in combination to clarify the regulatory relationships between these pathways. Furthermore, a mouse model of diabetic kidney disease was established and treated with isorhamnetin via intragastric administration. Blood glucose and renal function parameters were measured, renal histopathological changes were examined, and alterations in podocyte marker proteins, inflammasome activation, pyroptosis, mitochondrial damage, and the cGAS-STING pathway in kidney tissues were analyzed. Results: Isorhamnetin alleviated high glucose-induced abnormalities in podocyte marker proteins and cellular injury. It also inhibited NLRP3 inflammasome activation, thereby attenuating pyroptosis. Furthermore, isorhamnetin stabilized mitochondrial membrane potential, decreased mitochondrial ROS production, suppressed excessive opening of the mitochondrial permeability transition pore, alleviated mitochondrial damage, and reduced cytosolic mtDNA release, which in turn suppressed activation of the cGAS-STING pathway. Knockdown of STING inhibited high glucose-induced NLRP3-dependent pyroptosis. Consistently, isorhamnetin improved renal function in mice with diabetic kidney disease, attenuated glomerulosclerosis and fibrosis, and markedly suppressed mitochondrial damage, mtDNA leakage, cGAS-STING activation, and NLRP3-mediated pyroptosis and inflammatory responses in renal tissues. Conclusions: Isorhamnetin treatment attenuates diabetic kidney disease by improving mitochondrial homeostasis and inhibiting the cGAS-STING/NLRP3 inflammasome pathway.
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Materials Today Bio
·
2026
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IF 11
Zang Xin,Liu Dezhi,Zhang Jingyi,Chao Xuyuan,Chen Xin,Yang Shengjie,Fang Yingying,Li Yan,Li Yinjuan,Qi Lu,Wang Xinghe
In triple-negative breast cancer (TNBC), tumor-associated macrophages (TAMs) and tumor-infiltrating dendritic cells (TIDCs) often exhibit an immunosuppressive phenotype. This myeloid-dominant milieu reinforces an immune-cold state, promotes metastasis and contributes to immunotherapy resistance. In this study, we developed a mannose-functionalized graphene oxide nanocarrier (GO-EDM) with favorable biocompatibility and high NIR photothermal conversion efficiency. Docetaxel and vadimezan (DMXAA), a prototypical STING agonist, were co-loaded into GO-EDM to generate GO-EDM-DTX-Vad. In vitro, the nanocomposite promoted M2-to-M1 repolarization, thereby attenuating pro-tumor paracrine signaling from M2 macrophages and limiting TNBC cell proliferation, migration and invasion. Concomitantly, it promoted dendritic cell maturation and induced immunogenic cell death (ICD) in tumor cells, collectively enhancing antigen presentation and T-cell activation. In vivo, both intratumoral administration and systemic intravenous administration of GO-EDM-DTX-Vad effectively suppressed primary tumor growth. In a lung metastasis model, when combined with 808 nm NIR irradiation, the pulmonary metastatic burden was significantly reduced. Specifically, this treatment reduced the accumulation of M2 macrophages, MDSCs and Tregs within tumors, while promoting DC maturation and increasing intratumoral infiltration of M1 macrophages, CD8 + T cells and memory T cells. Taken together, GO-EDM-DTX-Vad leverages passive tumor accumulation and mannose receptor–guided dual targeting of TAMs and TIDCs to integrate DTX-based chemotherapy, STING-mediated immune activation and mild NIR photothermal therapy. This integrated chemo–photothermal–immunotherapeutic design couples direct tumor cell killing with myeloid reprogramming and immune activation, offering a unified strategy for metastatic TNBC.
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Materials Today Bio
·
2026
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IF 11
Xiaoqing Zhou,Guangyun Hu,Can Huang,Ying Liu,Zhou-rui Ma,Yuangang Lu,Yong Xu,Wei Qian
Intractable wounds remain a major clinical challenge due to persistent oxidative stress, dysregulated inflammation, and impaired macrophage polarization. Here, we develop a therapeutic cryogel by integrating ultrasmall Prussian blue (USPB) nanozymes into a GelMA–quaternary ammonium chitosan methacryloyl matrix via cryogelation. The resulting Cryogel@USPB features high porosity, large interconnected pores, and strong swelling capacity, supporting its application in wound environments. Cryogel@USPB exhibits potent catalase-, peroxidase-, and superoxide dismutase-like activities, enabling efficient ROS scavenging. In vitro, it promotes macrophage polarization toward a regenerative phenotype and suppresses pro-inflammatory cytokines. In vivo, Cryogel@USPB significantly accelerates healing in deep second-degree burn and diabetic wound models, achieving wound closure rates of 94.07 ± 1.94% and 98.69 ± 1.02%, respectively, with improved skin structure and collagen deposition. Mechanistically, Cryogel@USPB modulates the wound microenvironment by inhibiting cGAS–STING signaling. These findings identify Cryogel@USPB as a promising immuno-regulatory nanozyme platform for treating complex wounds.
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IMMUNOBIOLOGY
·
2026
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IF 3.1
Yingying Yang,Yuanqiu Zhong,Fanghua Liu,Shougang Liu,Yongfeng Chen
Here, we investigated the role of protein tyrosine phosphatase nonreceptor type 2 (PTPN2) in psoriasis pathogenesis, focusing on its regulation of the stimulator of interferon genes–signal transducer and activator of transcription 3 (STING–STAT3)-autophagy axis. Using cellular and imiquimod-induced mouse models, we assessed PTPN2 expression and function using multiple techniques, including immunofluorescence, co-immunoprecipitation, and Western blotting. A significant downregulation of PTPN2 expression was observed in psoriatic tissues. We established that PTPN2 directly interacts with STING and regulates its phosphorylation, with direct evidence from catalytic-dead PTPN2 mutant experiments showing that PTPN2's dephosphorylation of STING is activity-dependent. PTPN2 overexpression curbed keratinocyte proliferation, stimulated apoptosis and autophagy, and reduced the secretion of proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin (IL) 23 subunit alpha (A), and IL-17A. The application of a STING agonist mitigated these effects, whereas STAT3 inhibition restored them. PTPN2 overexpression attenuated psoriatic pathology, and this therapeutic benefit was further enhanced by co-administering the autophagy inducer rapamycin. Collectively, our results delineate a novel mechanism by which PTPN2 alleviates psoriasis-like pathology in keratinocytes by targeting the STING–STAT3 pathway and promoting autophagy and apoptosis. These findings indicate that PTPN2 is a potential therapeutic target, with in vivo validation supporting its translational relevance.
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JOURNAL OF CONTROLLED RELEASE
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2026
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IF 12.4
Keqiang Lu,Yaoquan Su,Xingchen Zhou,Fang Zhang,Xueping Zeng,Zikun Wang,Jiayu Gu,Yunyun Zhou,Jinfeng Liu,Juanjuan Peng,Lingzhi Zhao
Conventional reactive oxygen species (ROS)-mediated tumor therapies such as photo-, sono-, and chemodynamic therapies are often limited by inadequate penetration depth of external stimuli and insufficient endogenous ROS substrates (e.g., O₂ and H₂O₂). Here, we report that horseradish peroxidase (HRP) can catalyze artemisinin to generate ROS. Based on this, a “ROS bomb” nanomedicine was designed for antitumor immunotherapy. The nanocarrier consists of silica cross-linked micelles incorporating ROS-cleavable thioketal bonds and encapsulated artemisinin as the payload, with surface-immobilized HRP serving as the trigger. Within the tumor microenvironment with elevated H₂O₂, the thioketal linkers are cleaved to release artemisinin, initiating an HRP-catalyzed ROS cascade. The ROS burst induces immunogenic cell death and activates the STING pathway in dendritic cells assisted by the co-released drug SN38, effectively suppressing the growth of immunosuppressive triple-negative breast tumors. This exogenous ROS delivery strategy overcomes the restrictions of conventional ROS therapies, offering a potent approach for treating deep-seated tumors.
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Advanced Science
·
2026
·
IF 14.1
Yuelan Wu,Wenbo Geng,Qinjin Dai,Wanyun Zhang,Yuxian Lai,Pei Zhang,Chunjiang Zhou,Yinuo Wang,Qingfeng Cao,Xiang Luo,Yujie Lai,Changwei Huang,Peizeng Yang
Autoimmune uveitis is a sight-threatening inflammatory disease in which the cGAS-STING signaling pathway exacerbates inflammation by recognizing excessive cell-free DNA (cfDNA). However, conventional cfDNA scavengers have limited blood-retinal barrier penetration, and monotherapies cannot control the complex inflammatory network. Herein, we developed a cationic poly(disulfide)-drug nanoplatform (LA/DexP), which self-assembled via salt bridge interactions and aggregation-induced polymerization between a guanidyl-functionalized lipoic acid derivative (LA) and dexamethasone phosphate (DexP). This platform is designed to synergistically inhibit the cGAS-STING pathway and achieve efficient intraocular drug delivery. LA/DexP functioned as an efficient scavenger of cfDNA through electrostatic interaction, thereby inhibiting cGAS-STING overactivation. Meanwhile, it leveraged thiol-disulfide exchange to enhance blood-retinal barrier penetration, achieving a 5.09-fold higher apparent permeability coefficient than free DexP, and exhibited ROS-responsive drug release. In an experimental autoimmune uveitis mouse model, LA/DexP treatment significantly reduced cfDNA levels and inhibited cGAS-STING signaling. It also downregulated pro-inflammatory cytokine expression, promoted macrophage polarization from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype, and rebalanced Th1/Th17-Treg cell subsets. These combined effects effectively inhibited uveitis severity. In summary, this study establishes a highly barrier-permeable nanoplatform that synergistically integrates drug delivery with cGAS-STING pathway inhibition, offering a promising therapeutic strategy for autoimmune uveitis.
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Discover Nano
·
2026
·Vol. 21
·期 1
·415
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IF 6.7
Long Lin,Zhang Yexi,Xiao Jun,Zang Jianhua
Purpose To fabricate hesperetin-loaded fucoidan-selenium (Hes/Fu-Se) nanoparticles (NPs) for alleviating cisplatin-induced acute kidney injury (AKI), overcoming hesperetin’s low solubility and bioavailability and boosting antioxidant and anti-inflammatory efficacy. Methods Hes/Fu-Se NPs were prepared by encapsulating hesperetin within fucoidan, and then functionalized selenium (Se) NPs. Nanoparticle physicochemical properties and antioxidant activity (FRAP, ABTS) were characterized. Cisplatin-stimulated HK-2 cells were used for in vitro detection of cell viability, apoptosis, ROS accumulation, mitochondrial function and cGAS-STING signaling. A cisplatin-induced AKI mouse model was adopted to test renal biochemical indexes, renal histopathology and renal injury-related protein expression. Results Synthesized Hes/Fu-Se NPs exhibited uniform particle size, superior aqueous solubility and potent antioxidant activity. In vitro, the NPs restored HK-2 cell viability, mitigated apoptosis and ROS overproduction, and inhibited DNA damage and cGAS-STING cascade activation. In vivo, Hes/Fu-Se markedly reduced serum BUN and CRE, alleviated renal histological lesions and inflammatory infiltration, and downregulated the expression of cGAS, STING, γH2AX and TNF-α in kidney tissues. Conclusions Hes/Fu-Se NPs relieve cisplatin-triggered AKI via amplified antioxidation, DNA damage restoration and cGAS-STING pathway suppression. This nanoformulation provides a promising nephroprotective strategy against chemotherapy-related renal toxicity for clinical translation. Graphical abstract
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ACS Applied Materials & Interfaces
·
2025
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IF 8.2
Ling Yu,Fengkai Qiu,Yumin Hu,Tingting Liao,Mengqian Zhai,Ronghua Wu,Qianhui He,Huilin Hu,Shuiwei Xia,Junguo Hui,Zufei Wang,Yang Yang,Rongfang Qiu,Minjiang Chen,Weiqian Chen,Jianfei Tu,Jiansong Ji,Chenying Lu
Because of the high incidence and mortality of cancer, there is an urgent need for more effective tumor diagnostic imaging and treatment strategies. Single-molecule therapeutics have emerged as a promising strategy to address the limitations of independent imaging and therapeutic modalities, thereby significantly reducing adverse side effects for patients. For the first time, we successfully synthesized NaGd(MoO4)2 nanoparticles via a homogeneous precipitation method in polyol media, which serve as a single-molecule agent for MRI imaging and metallic immunotherapy. With the addition of iRGD, we obtained iRGD-NaGd(MoO4)2. The iRGD-NaGd(MoO4)2 nanoparticles exhibit excellent tumor-targeting capability and significantly enhance T1-weighted MRI contrast with a longitudinal relaxivity of 4.95 mM–1 s–1. In terms of antitumor immunotherapy, iRGD-NaGd(MoO4)2 not only directly activates the cGAS-STING pathway but also induces ferroptosis in tumor cells, resulting in the generation of aberrant dsDNA and thereby indirectly activating the STING pathway. The dual pathway elicits a tumor-specific immune response, plays a significant role in promoting the maturation of DC cells, activates DC and T cells to secrete high levels of TNF-α, IL-6 and other cytokines, and regulates the polarization of macrophages from M2 phenotype to M1 phenotype. This mechanism significantly suppresses tumor growth. Beyond the metallic immunotherapy induced by Mn2+, Zn2+, and Co2+, this study provides robust validation of MoO42– as an effective cGAS-STING agonist. Moreover, this study achieved the synergy of multiple disciplines including biomaterials, tumor immunotherapy and medical imaging. This not only promotes the innovative integration in various fields, but also provides new treatment strategies and imaging tools for cancer treatment, which has important clinical application prospects.
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PLoS One
·
2025
·Vol. 20
·期 6
·e0325704
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IF 2.6
Yuelong Zhang,Xunshan Ren,Huangming Zhuang,Huajie Li,Miradj Siddick Adam,Rongling Feng,Junming Zhu,Panghu Zhou
Osteoarthritis (OA), characterized by synovial inflammation, articular cartilage degeneration, and structural changes of subchondral bone and periarticular tissues, represents a major unmet clinical challenge. Targeting senescent chondrocytes has emerged as a promising therapeutic strategy of OA. Human umbilgratical cord mesenchymal stem cells (hUCMSCs) have shown potential in OA treatment through paracrine mechanisms, but their clinical translation is limited by challenges in cell viability control and safety concerns. hUCMSCs decellular extracellular matrix (hUCMSCs-dECM) can target senescent chondrocytes to alleviate senescence in OA. Stimulator of interferon gene (STING) can promote chondrocyte senescence in OA through the activation of NF-κB signaling, and inhibition of STING may provide a novel approach for OA treatment. Here, we demonstrated that hUCMSCs-dECM attenuated chondrocyte senescence in vivo and in vitro by inhibiting the STING-NF-κB pathway, which would provide a novel approach for OA treatment.
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