Pharmaceutics
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2024
·Vol. 16
·期 9
·1216
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IF 4.9
Zhijun Miao,Xue Song,Anan Xu,Chang Yao,Peng Li,Yanan Li,Tao Yang,Gang Shen
Background:Activating the cytosolic innate immune sensor, the cGAS-STING pathway, holds great promise for enhancing antitumor immunity, particularly in combination with immune checkpoint inhibitors (ICIs). However, the clinical application of STING agonists is often hindered by poor tumor accumulation, limited cellular uptake, and rapid clearance. To address these challenges, we developed a human serum albumin (HSA)-based nanoreactor system for the efficient delivery of the STING agonist SR-717, aiming to improve its antitumor efficacy.Methods:Using a biomineralization technique, we encapsulated SR-717 within HSA nanocages to form SH-NPs. These nanoparticles were characterized in terms of size, stability, and cellular uptake, and their ability to activate the STING pathway was assessed in both in vitro and in vivo models, including freshly isolated human renal tumor tissues. In vivo antitumor efficacy was evaluated in a murine renal tumor model, and immune responses were measured.Results:SH-NPs exhibited enhanced stability, efficient cellular uptake, and superior tumor accumulation compared to free SR-717. They robustly activated the STING pathway, as evidenced by increased phosphorylation of TBK1 and IRF3, along with elevated IFN-β production. Additionally, SH-NPs reshaped the immunosuppressive tumor microenvironment, promoting T-cell-mediated immunity and improving the therapeutic efficacy of checkpoint blockade in murine models. The validation in human renal tumor tissues further highlighted their potential for clinical translation. Importantly, SH-NPs were well tolerated with minimal systemic toxicity.Conclusions:This study underscores the potential of HSA-based nanoparticles for the targeted delivery of STING agonists, effectively enhancing antitumor immunity and improving cancer immunotherapy outcomes. SH-NPs offer a promising solution to the limitations of current STING agonists in clinical settings.
研究领域:
肿瘤学
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药学
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免疫学
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纳米技术
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2024
·
IF 12.8
Haixia Wang,Zheng Liu,Youqiang Fang,Xing Luo,Chunxiong Zheng,Yanteng Xu,Xiangfu Zhou,Qing Yuan,Shixian Lv,Limin Ma,Yeh-Hsing Lao,Yu Tao,Mingqiang Li
Immunotherapy through the activation of the stimulator of interferon genes (STING) signaling pathway is increasingly recognized for its robust anti-tumor efficacy. However, the effectiveness of STING activation is often compromised by inadequate anti-tumor immunity and a scarcity of primed immune cells in the tumor microenvironment. Herein, we design and fabricate a co-axial 3D-printed scaffold integrating a non-nucleotide STING agonist, SR-717, and an AKT inhibitor, MK-2206, in its respective shell and core layers, to synergistically enhance STING activation, thereby suppressing tumor recurrence and growth. SR-717 initiates the STING activation to enhance the phosphorylation of the factors along the STING pathway, while MK-2206 concurrently inhibits the AKT phosphorylation to facilitate the TBK1 phosphorylation of the STING pathway. The sequential and sustained release of SR-717 and MK-2206 from the scaffold results in a synergistic STING activation, demonstrating substantial anti-tumor efficacy across multiple tumor models. Furthermore, the scaffold promotes the recruitment and enrichment of activated dendritic cells and M1 macrophages, subsequently stimulating anti-tumor T cell activity, thereby amplifying the immunotherapeutic effect. This precise and synergistic activation of STING by the scaffold offers promising potential in tumor immunotherapy.
研究领域:
癌症免疫疗法
·
生物材料
·
药学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
Journal of Inflammation Research
·
2022
·
IF 4.631
Renhui Huang,Qi Shi,Shutian Zhang,Hong Lin,Chengzhi Han,Xinyi Qian,Yijun Huang,Xiaorong Ren,Jiayuan Sun,Nana Feng,Chunmei Xia,Meng Shi
Purpose: Endoplasmic reticulum stress (ERS) plays an important role in the pathogenesis of lung ischemia/reperfusion (I/R) injury. Cyclic GMP-AMP synthase (cGAS) is a cytosol dsDNA sensor, coupling with downstream stimulator of interferon genes (STING) located in the ER, which involves innate immune responses. The aim of our present study was to investigate the effects of cGAS on lung I/R injury via regulating ERS.Methods: We used Sprague-Dawley rats to make the lung I/R model by performing left hilum occlusion-reperfusion surgery. cGAS-specific inhibitor RU.521, STING agonist SR-717, and 4-phenylbutyric acid (4-PBA), the ERS inhibitor, were intraperitoneally administered in rats. Double immunofluorescent staining was applied to detect the colocalization of cGAS or BiP, an ERS protein, with alveolar epithelial type II cells (AECIIs) marker. We used transmission electron microscopy to examine the ultrastructure of ER and mitochondria. Apoptosis and oxidative stress in the lungs were assessed, respectively. The profiles of pulmonary edema and lung tissue injury were evaluated. And the pulmonary ventilation function was measured using a spirometer system.Results: In lung I/R rats, the cGAS-STING pathway was upregulated, which implied they were activated. After cGAS-STING pathway was inhibited or activated in lung I/R rats, the ERS was alleviated after cGAS was inhibited, while when STING was activated after lung I/R, ERS was aggravated in the AECIIs, these results suggested that cGAS-STING pathway might trigger ERS responses. Furthermore, activation of cGAS-STING pathway induced increased apoptosis, inflammation, and oxidative stress via regulating ERS and therefore resulted in pulmonary edema and pathological injury in the lungs of I/R rats. Inhibition of cGAS-STING pathway attenuated ERS, therefore attenuated lung injury and promoted pulmonary ventilation function in I/R rats.Conclusion: Inhibition of the cGAS-STING pathway attenuates lung ischemia/reperfusion injury via alleviating endoplasmic reticulum stress in alveolar epithelial type II cells of rats.
研究领域:
免疫学
·
病理生理学
·
呼吸医学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Materials Today Nano
·
2024
·
IF 8.2
Chen Wang,Qiliner Feng,Hongli Lu,Qiubei He,Peng Zhang,Junjie Tang,Zhuoyin Liu,Jie Liu,Baizhu Chen
The mitochondrial energy metabolic reprogramming of tumors leads to the hypoxic, acidic, and immunosuppressive microenvironment. To regulate the reprogrammed mitochondrial energy metabolism and the abnormal tumor microenvironment (TME) intracellularly and extracellularly, herein, we purposely constructed the metabolic regulating and immunological activating nanocomposites (NCs) formed by the manganese dioxide (MnO 2 ) nanoparticles loaded with lactate oxidase (LOX), dichloroacetic acid (DCA) and SR-717, camouflaged by the cell membrane of tumors. After the NCs targeting to the tumors, the loaded DCA inhibited the glycolysis and triggered the produced pyruvate into mitochondria for further degradation. DCA also reduced the amount of CD39 and CD73, thereby promoting the accumulation of ATP intracellularly. The cascade of MnO 2 and LOX catalyzed the lactate to pyruvate together with oxygen for the relief of the hypoxic and immunosuppressive TME. The regulation of the mitochondrial metabolism together with the degradation of lactate contributed to activating the immune cells. Meanwhile, the loaded SR-717 together with the release of Mn 2+ activated the cyclic guanosine monophosphate adenosine monophosphate synthase/interferon gene stimulator signaling pathway for efficient antitumor effects and immunotherapy. Taken together, the designed multifunctional nanocomposites realized an effective tumor immunotherapy by regulating the reprogrammed mitochondrial energy metabolism intracellularly, relieving the abnormal TME and activating the innate antitumor immunological effects extracellularly. Our work established an approach to the enhanced immunotherapy by regulating the reprogrammed metabolism for efficient cancer treatment.
研究领域:
癌症生物学
·
免疫学
·
纳米技术
·
生物化学
·
药理学
✓ 已验证
产品关联
DOI
高影响因子
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