JOURNAL OF NANOBIOTECHNOLOGY
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2025
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IF 12.6
Zhicheng Zhang,Xiaoyan Sun,Yaxin Qin,Yufan Yang,Qi Dai,Xiaoyan Bao,Minoru Suzuki,Sheng Wang,Zai Yang,Zhifeng Li,Min Han,Donghang Xu,Qichun Wei
Boron Neutron Capture Therapy (BNCT) offers selective tumor cell ablation with minimal damage to normal tissues, but its efficacy is limited by therapy-induced immunosuppression and high intratumoral H 2 O 2 levels, restricting synergy with immunotherapy. Here, we report BSA-BPA-MnO 2 , a tumor microenvironment-responsive, manganese-enriched nanoboron agent designed to overcome these barriers. This nanoplatform combines efficient boron delivery with Mn 2+ -driven Fenton-like catalysis and cGAS-STING pathway activation, amplifying BNCT-induced oxidative stress and inducing immunogenic pyroptosis alongside robust type I interferon signaling. This dual mechanism transforms BNCT from a local therapy into a systemic immune activator, enhancing dendritic cell maturation and CD8 + T cell responses. Additionally, MnO₂ enables MRI-guided BNCT, integrating diagnostics and therapeutics. Notably, the platform achieves potent tumor suppression and systemic immune activation even at subclinical boron levels, offering a promising strategy for next-generation immune-integrated BNCT, particularly against melanoma.
研究领域:
癌症免疫治疗
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纳米医学
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放射肿瘤学
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分子影像学
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免疫代谢
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生物医学工程
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Advanced Science
·
2026
·
IF 14.1
Shuang Liang,Yiwei Tian,Feiyu Zhao,Yue Han,Kongshuo Ma,Linna Hai,Kaiqing Yun,Yueyang Zhao,Siqi Zhang,Ziyi Zhang,Yuxuan Peng,Kuan Hu,Jing Zhong,Bai Xiang,Zhaohui Wang
The cGAS-STING pathway, a critical cytosolic DNA-sensing mechanism in innate immunity, holds significant promise for cancer immunotherapy. However, conventional DNA-damaging therapies lack tumor specificity and cause damage to normal tissue. Furthermore, dendritic cells (DCs), central to the STING-mediated immune response, exhibit extrinsic immunosuppression via inhibitory receptors such as T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), which impairs DNA internalization and subsequent pathway activation. Herein, we engineered a telomere stress-induced nanoreactor composed of a pH-responsive zeolitic imidazolate framework-8 encapsulating telomerase-targeted 6-thio-2’-deoxyguanosine (6-thio-dG), with TIM-3 antibodies (αTIM-3) adsorbed onto its surface. Following accumulation in the tumor, the nanoreactor degrades within the acidic tumor microenvironment, releasing 6-thio-dG to induce tumor cell-specific telomeric DNA damage. Concurrently, the αTIM-3 blocks TIM-3 receptors on DCs, thereby enhancing their internalization of the released DNA. This dual-action strategy drives robust cGAS-STING activation, enhancing type I interferon production and DCs maturation. In murine models of immunogenic and poorly immunogenic tumors, the nanoreactor significantly suppresses tumor growth and prolongs survival. By coupling tumor-intrinsic telomere stress with DC-extrinsic checkpoint inhibition, this work establishes a precision platform for cGAS-STING pathway activation, presenting a promising therapeutic strategy for telomerase-positive malignancies.
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Science Advances
·
2026
·Vol. 12
·期 2
·
IF 12.5
Qi Shang,Chenwei Jiang,Mingmei Guo,Minglu Tang,Jiapei Yang,Junjie Xie,Xiaoran An,Qiang Zhang,Feihu Wang
Glioblastoma multiforme (GBM), the most aggressive primary brain tumor, demonstrates persistent resistance to immunotherapy due to its profoundly immunosuppressive microenvironment and markedly limited T cell infiltration. In this context, we engineered a STING agonist–incorporated prodrug hydrogel that orchestrates dual activation of innate and adaptive immunity to prevent postoperative GBM recurrence. We found that this in situ–forming hydrogel integrates seamlessly with tumor resection procedures, serves as a drug depot for sustained tumoral releases of therapeutic agents, and thus reprograms the tumor microenvironment by promoting M1 macrophage polarization, suppressing regulatory T cell activity, and enhancing cytotoxic T lymphocyte infiltration, thereby establishing a robust antitumor immune response. As a postoperative adjuvant therapy, the hydrogel effectively inhibits orthotopic GBM recurrence and extends animal survival while establishing durable immune memory against tumor rechallenge. Our findings demonstrate the translational potential of immunologically engineered hydrogels for STING-activated immunotherapy in preventing postresection GBM recurrence.
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JOURNAL OF NANOBIOTECHNOLOGY
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2026
·
IF 12.6
Wu Zhiming,Zeng Jiamin,Feng Longbao,Zhu Xiongjie,Guo Rui,Feng Weici,Deng Wei
Non-muscle-invasive bladder cancer (NMIBC) carries 70% incidence yet remains plagued by high recurrence because single-modality chemotherapy or immunotherapy is crippled by rapid urinary clearance, poor tumor specificity, and narrow therapeutic windows. To overcome these challenges, we develop a homologous-targeted cerium nanozyme (HMZCO/DS@CM) that co-loads doxorubicin and the STING agonist MSA-2 in Mn/Zr-co-doped CeO₂ cores camouflaged with tumor-cell membranes. We discover that Mn/Zr substitution accelerates Ce³⁺/Ce⁴⁺ redox cycling, sustaining peroxidase- and SOD-like activities to deplete glutathione and amplify reactive oxygen species, thereby synchronizing immunogenic cell death with STING activation. The tumor cell membrane coating prolongs circulation, evades immune recognition, and directs NMIBC-homing, enabling pH-responsive, spatially and temporally controlled delivery co-release of both drugs within tumors. In orthotopic NMIBC models, HMZCO/DS@CM achieves five-fold tumor enrichment versus monotherapy, unleashes potent systemic immunity, blocks recurrence and metastasis with negligible toxicity. Collectively, this catalytic nanozyme–membrane nanoplatform transforms intravesical instillation into a sustained-release chemo-immunotherapy depot, reactivating local antitumor immunity and reducing NMIBC recurrence, thereby offering a practical adjuvant strategy with minimal systemic impact. Graphical
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Theranostics
·
2026
·Vol. 16
·期 4
·1720
·
IF 13.3
Bingchun Zeng,Kai Ling,Qingpeng Yuan,Zeyang Chen,Guangrong Zhang,Wenyue Kang,Xuanjun Zheng,Chuanghong Liao,Youqing Mai,Zhongjie Huang,Ruibin Huang,Tiantian Zhai,Hongyan Jiang
Rationale: The efficacy of radiotherapy in triple-negative breast cancer (TNBC) is often limited by an immunosuppressive tumor microenvironment (TME), requiring high radiation doses that cause systemic toxicity. There is a critical need for theranostic strategies capable of guiding therapy and amplifying the efficacy of low-dose radiation. Methods: We developed a multifunctional organolutetium nanosensitizer (LSPA) for image-guided, low-dose radioimmunotherapy. Lutetium (Lu) serves as both a contrast agent for CT imaging and a radiosensitizer through the generation of reactive oxygen species (ROS). The LSPA nanoparticles were engineered to selectively accumulate in tumors and release their therapeutic payload in response to the acidic TME. Results: At a low 6 Gy X-ray dose, LSPA synergized with the PARP inhibitor Olaparib to induce extensive DNA damage. This activated the cGAS-STING pathway and remodeled the TME. The treatment promoted immunogenic cell death, dendritic cell maturation, and M1 macrophage repolarization. It also decreased regulatory T cells, leading to increased CD4 + and CD8 + T cell infiltration in both primary and metastatic tumors. Conclusion: This theranostic strategy suppressed primary and distant (abscopal) tumors, prevented recurrence, and established durable immune memory with low-dose irradiation. Our findings present a clinically translatable approach that combines a nanosensitizer with PARP inhibition to turn immunologically “cold” tumors into “hot” ones, thereby enhancing the efficacy of low-dose radioimmunotherapy while limiting systemic toxicity.
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Advanced Science
·
2026
·
IF 14.1
Kepeng Hu,Jiawei Wang,Wei Zhang,Zhixuan Wu,Jing Chen,Yujing He,Xiyue Duan,Yaoting He,Xin Xin,Haoyi Xiang,Yijing Wang,Chengwei Wu,Yang Yi,Qing Meng,Yuqian Qiao,Kui Cheng,Xiaojun Long,Zhangfa Song
The precise activation of the cGAS-STING pathway for effective tumor immunotherapy remains a significant challenge due to the complexity of immune responses and tumor microenvironment (TME) limitations. Here, a multifunctional nanoagonist, cRGD-PDA/ZIF8@ICG/TPT (cDZ@IP), was developed to realize nano-metabolite–driven multimodal synergistic activation of the STING pathway and enhanced immune recognition. The agonist combines cRGD peptide-targeted polydopamine-coated zeolitic imidazolate framework-8 with the photosensitizer indocyanine green and the chemotherapeutic drug topotecan. Upon near-infrared laser irradiation, cDZ@IP degrades within the TME, generating high levels of reactive oxygen species, inducing mitochondrial stress, and releasing endogenous mitochondrial DNA. Additionally, topotecan enhances DNA damage accumulation by inhibiting nuclear DNA repair. Zn 2 + released from the agonist further amplifies cGAS-STING pathway activation, thereby ensuring a robust immune response. The mild photothermal therapy-induced immunogenic cell death promotes the initiation of antitumor immunity, while also enhancing the effectiveness of immune checkpoint blockade. In vivo studies show that cDZ@IP significantly inhibits primary and distant tumor growth and prevents lung metastasis, providing a promising strategy for STING pathway-targeted cancer immunotherapy.
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Advanced Healthcare Materials
·
2026
·
IF 11
Jiajia Jia,Zhitong Guan,Jiaxin Wang,Ting Fang,Jiajun Sun,Aiyang Tong,Yingzhen Fan,Ming Zhao,Dongkai Wang,Zheran Wang,Ji Li
Although cGAS-STING immunotherapy holds immense potential, its efficacy is severely compromised by pathway evasion. To overcome this, we engineered a core-shell bilayer nanobomb (M/ZIF/MnO 2 @DBCO) via a template-assisted approach, integrating MSC1094308 into ZIF-8 cores followed by MnO 2 shell deposition and DBCO functionalization. In a simulated tumor microenvironment, ZIF-8 loading accelerated Mn 2+ release from MnO 2 , increasing the cumulative release by nearly 30% within 8 h compared to pristine MnO 2 . Cellular assays demonstrated rapid bio-orthogonal targeting of azide-modified tumors, achieving lysosomal escape within 6 h postuptake. Subsequently, MnO 2 -mediated glutathione (GSH) depletion and hydroxyl radical (·OH) generation, combined with Zn 2+ induced mitochondrial oxidative stress, produced cytotoxic reactive oxygen species (ROS) that triggered immunogenic cell death. Furthermore, Mn 2+ , Zn 2+ , and dsDNA released from damaged mitochondria cooperatively activated the cGAS-STING pathway. Concurrently, MSC1094308 inhibited ESCRT-mediated negative regulation, as evidenced by a ∼0.2 decrease in the p-STING/VPS4B-RFP colocalization coefficient, confirming the blockade of cGAS-STING evasion. In vivo studies revealed that the nanoplatform profoundly stimulated antitumor immunity, increasing tumor-infiltrating cytotoxic T lymphocytes approximately 8-fold versus untreated controls after 21 days. This work establishes an integrated strategy harnessing Zn 2+ /Mn 2+ synergy, nanobomb reactivity, and ESCRT inhibition to circumvent cGAS-STING evasion, offering a promising paradigm for cancer immunotherapy.
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Advanced Science
·
2026
·
IF 14.1
Chao Wang,Chenxuan Zhao,Yesong Yao,Zhiwen Zou,Anxin Shi,Zhuo Feng,Mingkang Yang,Yue Yu,Yang Liu,Xuehui Rui,Jinhui Wu
Intracellular nucleotide imbalance between ribonucleotides and deoxyribonucleotides can trigger cytosolic mitochondrial DNA (mtDNA) release and subsequent activation of the cGAS–STING pathway. However, fluoropyrimidine-induced nucleotide imbalance is constrained by their metabolic instability. Here, we leverage ribonucleotides to amplify floxuridine (FUDR)-induced mtDNA release and cGAS–STING activation for enhanced cancer chemoimmunotherapy. We identified that cytidine monophosphate (CMP) significantly enhances FUDR-mediated activation of the mtDNA-driven cGAS–STING pathway, inducing over 300-fold upregulation of the interferon gene Ifnb1 and initiating STING-dependent antitumor immunity. Genome-wide CRISPR-Cas9 screening identified five pyrimidine-metabolizing enzymes (CMPK1, CMPK2, TYMP, UPP1, and UPP2) that are responsible for the metabolic instability of floxuridine monophosphate (FdUMP). CMP and its intracellular metabolites can metabolically block these enzymes, thereby increasing the peak intracellular concentration of FdUMP by over 500-fold and extending its half-life by more than 20-fold, which in turn promotes sustained intracellular nucleotide imbalance. To translate this mechanism into therapy, we co-encapsulated FdUMP and CMP into hybrid lipid nanoparticles (FC-NPs). FC-NPs robustly activated STING-dependent antitumor immunity, achieving remarkable therapeutic efficacy in multiple murine colorectal cancer (CRC) models. Our study not only addresses the long-standing issue of fluoropyrimidine metabolic instability but also reveals a novel ribonucleotide-mediated immunomodulatory mechanism, providing a promising strategy to potentiate chemoimmunotherapy in CRC.
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高影响因子
Advanced Healthcare Materials
·
2026
·
IF 11
Bei Liu,Jiayi Zhang,Wenfei Xu,Yuechen Liu,Nawei Wu,Hongshang Peng,Hongxia Li,Zhaogang Sun,Hongqian Chu
Combinational photodynamic and immune checkpoint blockade (PDT/ICB) therapy is a promising approach for oncotherapy. However, the tumor microenvironment (TME) poses multiple biological barriers that can critically undermine the treatment outcomes of PDT/ICB. To this end, a cascade-amplified photodynamic immunotherapy nanoplatform based on the core-shell structured metal-organic frameworks (MOFs) was elaborately constructed. This nanoplatform, termed PMA, was constructed by growing manganese oxide (MnO 2 ) layer on a porphyrinic MOF core, followed by conjugation with PD-L1-targeting aptamers. Upon reaching the tumor, the MnO 2 shell scavenges glutathione (GSH) while concurrently releasing O 2 for hypoxia alleviation and Mn 2+ ions as STING agonists. Simultaneously, MOF-based core was directly self-assembled from porphyrin photosensitizers (PSs) and metal clusters, resulting in high PSs loading capacity without self-quenching. More importantly, the liberated PD-L1 aptamers block immune checkpoint interactions, reversing local immunosuppression and activating cytotoxic T lymphocytes. Together, this multimodal strategy evokes robust antitumor immunity, offering a powerful and translatable approach to expand the scope of cancer immunotherapy.
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BIOMATERIALS
·
2026
·
IF 13.6
Boyang Sun,Fuzhen Hu,Wenhao Dong,Silu Li,Xuedan He,Jonathan F. Lovell,He Ren,Yumiao Zhang
Lymph nodes serve as strategic targets for cancer vaccines by enhancing interactions with antigen-presenting cells (APCs) and promoting immune activation. Herein, we report that serum albumin can be chemically modified via in situ reduction with a short PEG linker, which subsequently coordinates with Mn 2+ to generate a lymph nodes targeting metallo-albumin nano-scaffold (MANS) capable of chelating His-tagged antigens and immunostimulatory adjuvants. Maintaining the “hitchhiking” effect of albumin, the MANS chelating antigens (E7 or AH1) accumulates in lymph nodes, where it triggers the responsive release of metal ions and adjuvants to synergistically activate the cGAS-STING pathway. Following uptake by bone marrow dendritic cells (BMDCs), MANS promoted the expression of maturation markers and cytokine release. In multiple murine TC-1 and CT26 tumor models, the MANS vaccine suppresses tumor growth and prolongs survival while elevating antigen-specific CD8 + T cells frequency by an order of magnitude; however, these effects were not observed in STING-knockout mice (STING-KO). The MANS vaccine also remodeled the tumor immune microenvironment (TME) by downregulating immunosuppressive cells in the tumor tissues with long-term immune memory, verified by a tumor rechallenge model.
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JOURNAL OF CONTROLLED RELEASE
·
2026
·
IF 12.4
Yaoqi Li,Chaogang Chen,Yu Ren,Kaiwei Wang,Yan Wang,Qingfeng Liu,Yitian Chen,Haixiang Si,Jing Tao,Xiaoliang Ding,Yong'’an Tang,Yibin Deng,Huabing Chen,Liyan Miao
Ionizing radiation-induced damage to the hematopoietic system is largely driven by STING activation-promoted M1 macrophage polarization and its resultant inflammation. However, effective suppression of pro-inflammatory macrophage polarization for treating radiation-induced hematopoietic stem cell injury is largely hindered by the inherent physiological barriers of bone marrow-targeted drug delivery. In this study, we develop a STING nanoinhibitor composed of poly(lactic- co -glycolic acid) nanoparticle loaded with a STING inhibitor and surface-coated senescent neutrophil membrane for targeted treatment of ionizing radiation-induced hematopoietic injury. Our STING nanoinhibitor can home to bone marrow via the CXCR4/SDF-1 axis and be phagocytosed by macrophages to shift activated pro-inflammatory M1 macrophages to the anti-inflammatory M2 phenotype through suppressing cGAS-STING signaling, and this STING inhibition can further reduce radiation-induced reactive oxygen species (ROS) accumulation to reduce M2-to-M1 macrophage polarization. In irradiation-treated mouse models, the STING nanoinhibitor preferentially accumulates in bone marrow to alleviate pancytopenia, preserve bone marrow architecture, and accelerate hematopoietic recovery while avoiding significant side effects. This study highlights the targeted modulation of bone marrow macrophages as a promising strategy for promoting hematopoietic cell recovery from radiation-induced injury.
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高影响因子
Science Advances
·
2026
·Vol. 12
·期 25
·eaea6844
·
IF 13.9
Jiaoting E,Yuxuan Zhao,Xiaoling Zhang,Qiuqi Zhang,Ying Xu,Shanshan Liu,He Ding,Jiuxin Zhu,Piaoping Yang,Rui Xie
Hepatocellular carcinoma (HCC) remains a challenge for therapeutic efficacy in converting cold tumors into hot ones. Herein, doping defect–engineered manganese perovskite piezoelectric nanocubes (Mn-BaZrO 3 , MBZO) integrated miltirone biomimetic delivery within tumor-derived nanovesicles are proposed for the parallel pyroptosis-apoptosis-necroptosis (PANoptosis) and the stimulator of interferon genes (STING) pathway activation to reshape the immune microenvironment, leading to tumor regression in HCC. Homologously targeting HCC cells, MBZO nanocubes accumulated and produced exogenous reactive oxygen species through the piezocatalytic effect. Specifically, miltirone accelerated oxidative stress amplification, potentially serving as an inducer of programmed cell death in HCC. Then, PANoptosis was activated to disrupt the cell barrier and release damage-associated molecular patterns, promoting immunogenicity. Concurrently, MBZO synergistically stimulated the STING pathway to evoke pro-inflammatory responses and elicit immunogenic cell death, triggering effector immune cell deployment (EICD). The piezobiomimetic delivery nanosystem bridged innate immunity activation and EICD to convert cold tumors into hot tumors and suppress tumor growth, thereby enhancing the efficacy of piezoimmunotherapy in HCC. A biomimetic nanomedicine activates PANoptosis and STING pathways to enhance the efficacy of liver cancer management.
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