Small
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2026
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IF 11.8
Min Mu,Bo Chen,Hui Li,Chenqian Feng,Susu Xiao,Rangrang Fan,Aiping Tong,Nianyong Chen,Gang Guo
Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, with limited efficacy of conventional therapies due to immunosuppressive tumor microenvironments and high recurrence. While bispecific T-cell engagers (BiTEs) show promise by engaging T cells against tumors, their clinical translation is hindered by poor stability, on-target off-tumor effect, and systemic toxicity. Herein, we develop a tumor-targeted nanozyme (MnO 2 -dsDNA@BiTE/APT) that co-delivers hydrolytically stable double-strand DNA (dsDNA: a STING agonist) and PD-L1/CD3 BiTE to overcome these limitations. The nanozyme leverages MnO 2 as a carrier for dsDNA, surface-loaded with BiTE via polyphenol-protein coordination, and functionalized with an aptamer (APT) for active targeting. Upon systemic administration, the nanozyme accumulates in tumors, releasing dsDNA, Mn 2+ , and BiTE. The synergistically activates the STING pathway to remodel the immunosuppressive microenvironment and enhances T cell-mediated cytotoxicity. This strategy represents a promising approach for potentiating immunotherapy in CRC by integrating innate immune activation with adaptive T cell engagement.
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PubMed
高影响因子
Asian Journal of Pharmaceutical Sciences
·
2026
·
IF 12.6
Xinying Wang,Xianlu Zhang,Zixuan Jiao,Shipeng Ning,Hanping Wang,Hui Liu,Lifen He,Haonan Li,Mingzhong Li,Kaiyuan Wang,Zhonggui He,You Pan
The treatment of triple-negative breast cancer (TNBC) is significantly hampered by its immunosuppressive tumor microenvironment and limited T-cell infiltration. Activating the STING pathway presents a promising therapeutic avenue due to its potential to trigger a robust innate immune response and remodel the immunosuppressive landscape, thereby sensitizing tumors to immunotherapy. To harness this potential, we developed an exosome-mimetic nanoplatform (EMMDs). EMMDs is fabricated by co-loading a disulfide-linked docetaxel prodrug (DTX-SS-PA) and the STING agonist MSA-2 into polymeric micelles and further decorated with homotypic tumor cell-derived exosomal membrane (EM). This biomimetic design confers superior tumor-targeting capability. Upon reaching the tumor site, the prodrug is specifically activated to release cytotoxic docetaxel (DTX), while MSA-2 is concurrently released to potently activate the STING pathway. This dual action initiates a powerful antitumor immune response and reverses immunosuppression, leading to a synergistic chemo-immunotherapeutic outcome. In the murine TNBC model, EMMDs demonstrated remarkable antitumor efficacy, obviously provoking a robust STING-mediated type I interferon response and inhibiting tumor growth. This work presents a promising biomimetic strategy for remodeling the tumor immune microenvironment via efficient STING activation.
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高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Yan Zhang,Chunhua Yin,Xiaoling Yuan,Shu Xu
Background Rheumatoid arthritis (RA) is a complex disorder characterized by joint synovitis, cartilage degradation, and bone destruction. Its etiology remains largely unexplored. This study aimed to investigate the potential roles of lactate and the underlying mechanisms contributing to RA pathogenesis. Methods A total of 10 adult patients with active RA and 10 matched patients with noninflammatory joint diseases, such as injuries or traumatic fractures, admitted to our hospital were enrolled in this research. Synovial tissues were collected from the participants. A collagen-induced arthritis (CIA) mouse model was established, and tissues were collected for isolation of synovial primary macrophages. The pathological characteristics of tissue samples were observed using H&E and safranin O staining. The THP-1 cells and mouse synovial primary macrophages were cultured and transfected. The level of dsDNA was evaluated using immunofluorescent staining and Qubit method. The production of proinflammatory cytokines was measured by ELISA kits. The activation of the cGAS-STING signaling pathway was confirmed by immunofluorescent staining, western blot and co-IP methods. Results The level of dsDNA in the synovial primary macrophage of RA patients and CIA mice was increased, accompanied by an increase in lactate levels. Lactate promoted the production of inflammatory cytokines in THP-1 cells and synovial primary macrophages from mice. Expression of cGAS was also elevated in synovial primary macrophages of RA patients and CIA mice. Lactate activated the cGAS-STING signaling pathway, while knockdown of cGAS inhibited the cytokine production. Knockdown of STING ameliorated the tissue damage in the CIA mouse model. Lactate exerted its proinflammatory effects through lactylation of cGAS, preventing its degradation and thereby activating the cGAS-STING signaling pathway to promote inflammation and exacerbate RA. Conclusion Lactate might activate the cGAS-STING signaling pathway, thereby accelerating RA progression in macrophages. This study identified a potential therapeutic target for the treatment of RA in the future.
研究领域:
免疫学
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风湿病学
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分子生物学
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炎症研究
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高影响因子
JOURNAL OF CONTROLLED RELEASE
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2025
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IF 11.5
Ruiqi Ming,Dingjie Suo,Zhongjie Wang,Shujun Liu,Chuyu Li,Chenguang Wang,Fan Zhang,Guihong Lu,Lin Mei,Li-Li Huang
The activation of stimulator of interferon genes (STING) pathways holds immense potential for cancer immunotherapy. Nevertheless, the challenge lies in achieving precise and efficient STING activation within tumors while avoiding systemic immunotoxicity. Here, we develop a novel nanotherapeutic platform, termed HAL@SyBVs, by simply electroporating FDA-approved prodrug 5-aminolevulinate hydrochloride (HAL) into the synthetic bacterial vesicles (SyBVs), which allows for the spatiotemporal orchestration of STING pathways. Following systemic injection, HAL@SyBVs target tumor tissues, where HAL induces the confined biosynthesis and accumulation of sonosensitizer protoporphyrin IX (PpIX) within mitochondria. Upon ultrasound irradiation, PpIX-induced reactive oxygen species (ROS) trigger the release of double-stranded DNA (dsDNA), thereby achieving precise STING activation. Simultaneously, SyBVs enhance STING signaling by impeding its degradation, thereby amplifying the immune response. This intelligent synergy effectively ameliorates the immunosuppressive tumor microenvironment and elicits a robust antitumor T cell immune response, resulting in comprehensive tumor regression without apparent adverse effects.
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BIOMATERIALS
·
2025
·
IF 12.9
Xiawei Zhou,Xiuhua Pan,Ziqi Shen,Ruixin Kang,Yueru Pang,Lin Luo,Feiyang Liu,Siyuan Yu,Jun Zhang,Qi Shen
Breast cancer remains a leading cause of cancer-related mortality in women, with intratumoral bacteria playing a significant role in immunosuppression. However, targeted therapeutic strategies to address this microbial influence remain underexplored. In this study, we developed a novel nanodrug bacteria biohybrid system, LGG-PDA@Cu-CPT, which integrated Lactobacillus rhamnosus GG (LGG) probiotics, polydopamine (PDA), and copper-irinotecan (Cu-CPT) composites to potentiate cancer immunotherapy by simultaneously eliminating immunosuppressive intratumoral bacteria and activating the cGAS–STING pathway, thereby suppressing tumor progression. Photothermal therapy (PTT) mediated by PDA enhanced intratumoral bacterial eradication by disrupting bacterial membranes and promoting intracellular Cu 2+ uptake. Cu 2+ ions further induced reactive oxygen species (ROS) generation through Fenton-like reactions, effectively killing intratumoral Fusobacterium nucleatum (Fn) bacteria and thereby relieving the bacterium-induced immunosuppressive tumor microenvironment. Concurrently, the acidic tumor microenvironment and PTT-induced heating facilitated the release of CPT, which, together with LGG , activated the cGAS-STING pathway. This activation triggered robust type I interferon production, dendritic cell (DC) maturation, and cytotoxic T lymphocyte (CTL) infiltration, leading to effective immune-mediated tumor cell clearance. Additionally, Fn bacterial remnants acted as immunostimulatory agents, further amplifying immune responses. This synergistic strategy of bacterial elimination and cGAS-STING activation significantly enhanced antitumor immune responses and inhibited tumor progression, providing a promising therapeutic approach for breast cancer treatment.
研究领域:
癌症生物学
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免疫学
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纳米医学
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微生物学
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药理学
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高影响因子
TOXICOLOGY LETTERS
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2026
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IF 2.9
Liwei Yang,Zhili Ge,Xuehan Ding,Jingjing Shi,Jiaxin Zhang,Tianyou Wang,Huibin Jiang,Xinyu Zhang,Liting Zhou
Tributyl phosphate (TBP) can lead to abnormal hepatic lipid metabolism. Inflammation triggered by the cGAS-STING may be involved in it. Within this research, we investigated the involved mechanisms of TBP-induced lipid metabolic disorders. Rats and BRL-3A cells are used as models to determine the liver toxicity of TBP. Aspirin was used to alleviate the inflammation induced by TBP. RU.521 and H151 were employed to inhibit the activation of cGAS-STING. HE staining was applied to observe liver injury. The mitochondrial structure was observed with transmission electron microscopy. The quantification of lipid levels was achieved through colorimetry. The concentrations of inflammatory factors were assessed by ELISA. The expression levels of genes involved in lipid metabolism and cGAS-STING signaling pathway were detected by Q-PCR and western blot. TBP induced hepatocyte swelling and disorganized cord structures of rat livers. Following exposure to TBP, there is an elevation in the concentrations of triglycerides (TG) and total cholesterol (T-CHO), and the mRNA and protein expression levels of FASN, SREBP2, and PPARγ also showed a significant increase( P < 0.05). TBP exposure enhanced interleukin-6 (IL-6) production and this effect is reversed by aspirin treatment( P < 0.05). In BRL-3A cells, inhibiting cGAS-STING signaling pathway decreased the IL-6 concentrations and reversed the lipid accumulation caused by TBP( P < 0.05). Taken together, our results suggest TBP induced histopathological damage in rat livers, including hepatocyte swelling and disorganized cord structures. It also caused alterations in mitochondrial structure. Moreover, TBP can mediate inflammatory responses via the cGAS-STING, which in turn leads to hepatic lipid accumulation.
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JOURNAL OF NANOBIOTECHNOLOGY
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2026
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IF 15
Yuzhi Qiu,Yunting Liu,Sihan Chen,Yidi Liu,Xi Yu,Xiangliang Yang,Yan Zhang,Yanhong Zhu
Reprogramming tumor-associated macrophages (TAMs) from the pro-tumoral M2-like state to the immunostimulatory M1-like phenotype has emerged as a promising strategy for tumor therapy. However, most M2-like TAMs are preferentially located in hypoxic regions of the tumor, which are poorly accessible to many advanced drug delivery systems, posing a significant challenge to effective TAM reprogramming. Here, leveraging the tropism of facultative anaerobic bacteria to localize and propagate in the hypoxic tumor, an optogenetically engineered Escherichia coli Nissle 1917 strain conjugated with murine STING agonist (EcN flaB @UPD) was developed for cancer-specific immunotherapy. Upon near-infrared light illumination, the blue and UV emissions from upconversion nanoparticles (UCNPs) simultaneously activate the expression of Toll-like receptor (TLR) agonist, flaB, from EcN flaB , and the release of photocaged murine STING agonist, DMXAA, respectively. This spatiotemporally synchronized dual release ensures co-localized STING and TLR5 agonists inside the hypoxic niche, repolarizing TAMs from the M2 to the M1 phenotype via synergistic TLR5-MAPK1-NF-κB and STING-NF-κB signaling. The polarization of TAMs enhances their antigen-presenting capacity and, more importantly, activates the cytotoxic, stem-like and memory CD8 + T cells responses. This subsequently inhibits tumor growth, relapse, and metastasis in the murine 4T1 tumor model. Collectively, our work introduces the bacteria-based system that uses near-infrared light to dual-release immunotherapeutics for systemic anti-tumor immunity, opening new avenues for precise and effective cancer immunotherapy.
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高影响因子
Small
·
2025
·
IF 12.1
Jingjing Zhang,Fan Xie,Yunyang Zhang,Siying Chen,Wenjun Shi,Xinyan Yang,Yunjiu Ren,Yao Li,Mayakrishnan Arumugam,Xiangdong Kong,Ruibo Zhao
Dissolvable microneedle-based transdermal superficial technique demonstrates promised integrative potential for triple-negative breast cancer (TNBC) therapy, yet their insufficient mechanical strength restricts to puncture, attributed to the high-density tumor stroma and elasticity of TNBC, limiting long-distance therapeutics penetration and profound treatment in situ, posing a significant barrier to achieving effective therapy for TNBC management. Inspired by biomineralization, herein, a novel strategy is presented for a robust microneedle involving manganese phosphate biomimetic mineralization, which is characterized by a homogeneous inorganic–organic intercross modification, achieving high mechanical strength and solubility. Furthermore, the chemotherapy drug, doxorubicin (DOX), can be facilely integrated into this biomimetic process, facilitating chemoimmunological microneedles (MD-MN). Subsequently, the MD-MN provides high robustness for tumor injection followed by releasing manganese and DOX within the tumor, and the manganese can reduce tumor stroma and enhance deep DOX infiltration, exerting significant cancer cell apoptosis. Furthermore, manganese elements can reverse the immunosuppressive microenvironment by activating cGAS-STING, which taken together, constructs a boosted cascade chemoimmunological therapy for TNBC. These achievements present a successful integrative strategy for circulated cascade chemoimmunological treatment for TNBC, indicating a great potential of biomineralization-based cancer medicine, further demonstrating insights into biomimetic physiological reactions for material construction and translational medicine.
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JOURNAL OF CONTROLLED RELEASE
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2024
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IF 10.5
Kunguo Liu,Shiyu Du,Jiawei Yang,Juanjuan Li,Shijie Wang,Zhibin Zhang,Wen Luo,Chao Chen,Jingjing Yang,Xin Han
The immunosuppressive tumor microenvironment (TME) in solid tumors often impedes the efficacy of immunotherapy. Bacterial outer membrane vesicles (OMVs), as a promising cancer vaccine that can potently stimulate immune responses, have garnered interest as a potential platform for cancer therapy. However, the low yield of OMVs limits their utilization. To address this limitation, we developed a novel approach to synthesize OMV-like multifunctional synthetic bacterial vesicles (SBVs) by pretreating bacteria with ampicillin and lysing them through sonication. Compared to OMVs, the yield of SBVs increased by 40 times. Additionally, the unique synthesis process of SBVs allows for the encapsulation of bacterial intracellular contents, endowing SBVs with the capability of delivering catalase (CAT) for tumor hypoxia relief and activating the host cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway. To overcome the toxicity of lipopolysaccharide (LPS) on the SBVs surface, we decorated SBVs with a biocompatible polydopamine (PDA) shell, which allowed TME reprogramming using SBVs to be conducted without adverse side effects. Additionally, the photosensitizer indocyanine green (ICG) was loaded into the PDA shell to induce immunogenic cell death and further improve the efficacy of immunotherapy. In summary, the SBVs-based therapeutic platform SBV@PDA/ICG (SBV@P/I) can synergistically elicit safe and potent tumor-specific antitumor responses through combined immunotherapy and phototherapy.
研究领域:
肿瘤学
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免疫学
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纳米医学
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高影响因子
Theranostics
·
2025
·Vol. 15
·期 16
·8049
·
IF 13.3
Jiaorong Qu,Jianan Li,Le Wang,Yufei Li,Yinqiang Zhang,Jingtao Li,Zixuan Huo,Junsong Han,Runping Liu,Guifang Fan,Yinhao Zhang,Xiaoyong Xue,Xiaojiaoyang Li
Background and aims: Inducing the senescence of activated hepatic stellate cells (HSCs) has emerged as a promising therapeutic strategy for liver fibrosis, with potential connections to the Yes-associated protein (YAP)-controlled cGAS-STING pathway. However, the regulatory role of cytoskeletal dynamics on HSC senescence and its potential as a target for natural products have remained poorly understood. Methods: We employed preclinical in vivo and in vitro transcriptome analyses, experimental systems, Tmem173 -/- mice and liver-specific STING knockdown mice to demonstrate the anti-fibrotic effects and mechanism of ligustilide (LIG). Results: LIG selectively bound to monomeric globular actin (G-actin), thereby preventing its polymerization into polymeric filamentous actin (F-actin), which disturbed its interaction with intermediate filament component lamin A/C and initially destroyed the nuclear membrane. Moreover, the disruption of nuclear membrane caused YAP leakage from nuclear, which in turn suppressed lamin A/C and created a deleterious feedback loop that exacerbated nuclear membrane destabilization. Consequently, nuclear double stranded DNA (dsDNA) leakage caused by the above damage cascade ultimately triggered the activation of the cGAS-STING signaling pathway, promoting senescence-associated secretory phenotypes (SASPs) release and inducing HSC senescence. Moreover, the induction of HSC senescence and anti-fibrotic effects of LIG were completely abrogated in both whole-body STING knockout and liver-specific STING knockdown mice. Conclusions: By interacting with G-actin, LIG disrupted the cytoskeleton to compromise nuclear integrity with the involvement of YAP and further stimulated the cGAS-STING pathway, leading to the release of SASPs and HSC senescence, which ultimately mitigated liver fibrosis.
研究领域:
药理学
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细胞生物学
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分子生物学
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肝病学
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生物化学
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BIOMATERIALS
·
2024
·
IF 12.8
Yujun Zhang,Shijing Wang,Hyeonji Rha,Chang Xu,Yue Pei,Xiaoyuan Ji,Junmin Zhang,Ruitao Lu,Shaochong Zhang,Zhongjian Xie,Jong Seung Kim
Cancer immunotherapy has been developed to improve therapeutic effects for patients by activating the innate immune stimulator of interferon gene (STING) pathway. However, most patients cannot benefit from this therapy, mainly due to the problems of excessively low immune responses and lack of tumor specificity. Herein, we report a solution to these two problems by developing a bifunctional platform of black phosphorus quantum dots (BPQDs) for STING agonists. Specifically, BPQDs could connect targeted functional groups and regulate surface zeta potential by coordinating metal ions to increase loading (over 5 times) while maintaining high universality (7 STING agonists). The controlled release of STING agonists enabled specific interactions with their proteins, activating the STING pathway and stimulating the secretion release of immunosuppressive factors by phosphorylating TBK1 and IFN-IRF3 and secreting high levels of immunostimulatory cytokines, including IL-6, IFN-α, and IFN-β. Moreover, the immunotherapy was enhanced was enhanced mild photothermal therapy (PTT) of BPQDs platform, producing enough T cells to eliminate tumors and prevent tumor recurrence . This work facilitates further research on targeted delivery of small-molecule immune drugs to enhance the development of clinical immunotherapy.
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MATERIALS & DESIGN
·
2026
·
IF 8.2
Yuanxiang Yu,Wenjing Li,Yu Shao,Hairui Tian,Tingting Deng,Meili Li,Jiarui Li,Xuanhuan Ma,Zhenhao Li,Cong Huang,Wei Jiang,Xiaoxiao Luo
A phase-change nanocomposite enables light-triggered multimodal therapy and tumor-localized cisplatin release. • Photothermal and photodynamic stress induces mitochondrial DNA damage and cytosolic DNA sensing. • Innate immune activation drives immunogenic cell death, dendritic cell priming, and CD8+ T-cell infiltration. • The treatment achieves durable control and helps overcome immune resistance in triple-negative breast cancer. Activation of the GMP/AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway can sensitize tumors to immunotherapy, yet conventional photothermal therapy (PTT) or photodynamic therapy (PDT) alone rarely generates enough cytosolic double-stranded DNA (dsDNA) to fully engage this axis. Here we develop phase-change lauric-acid nanocomposites (CCL NPs) that co-load photothermal Cu 2-X S nanoparticles and cisplatin. After cellular uptake, near-infrared (NIR) irradiation induces synergistic PTT/PDT, and NIR-II heating melts the lauric-acid shell to trigger on-demand cisplatin release within tumors. The resulting ROS burst together with cisplatin causes extensive mitochondrial DNA damage and dsDNA leakage into the cytosol, leading to robust cGAS/STING activation. In tumor-bearing mice, CCL NPs promote dendritic-cell maturation and antigen cross-presentation, increase cytotoxic T-lymphocyte infiltration, and elicit immunogenic cell death, achieving durable tumor suppression with minimal systemic toxicity. Released copper further contributes via cuproptosis. Overall, CCL NPs integrate controllable chemotherapy with PTT/PDT to amplify innate immune sensing and drive effective antitumor immunity. Download: Download high-res image (164KB) Download: Download full-size image
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