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1Nanoparticles (NPs)-mediated Siglec15 silencing and macrophage repolarization for enhanced cancer immunotherapy显示文摘cell infiltration and proliferation in tumor tissues are the main factors that significantly affect the therapeutic outcomes of cancer immunotherapy.Emerging evidence has shown that interferon-gamma(IFN)could enhance CXCL9 secretion from macrophages to recruit T cells,but Siglec15 expressed on TAMs can attenuate T cell proliferation.Therefore,targeted regulation of macrophage function could be a promising strategy to enhance cancer immunotherapy via concurrently promoting the infiltration and proliferation of T cells in tumor tissues.We herein developed reductionresponsive nanoparticles(NPs)made with poly(disulfide amide)(PDSA)and lipid-poly(ethylene glycol)(lipid-PEG)for systemic delivery of Siglec15 siRNA(siSiglec15)and IFN for enhanced cancer immunotherapy.After intravenous administration,these cargo-loaded could highly accumulate in the tumor tissues and be efficiently internalized by tumor-associated macrophages(TAMs).With the highly concentrated glutathione(GSH)in the cytoplasm to destroy the nanostructure,the loaded IFN and si-Siglec15 could be rapidly released,which could respectively repolarize macrophage phenotype to enhance CXCL9 secretion for T cell infiltration and silence Siglec15 expression to promote T cell proliferation,leading to significant inhibition of hepatocellular carcinoma(HCC)growth when combining with the immune checkpoint inhibitor.The strategy developed herein could be used as an effective tool to enhance cancer immunotherapy.Xiaodi Liu Qi Zhang Yixia Liang Shiyu Xiong Yan Cai Jincheng Cao Yanni Xu Xiaolin Xu Ye Wu Qiang Lu Xiaoding Xu Baoming Luo 2023Acta Pharmaceutica Sinica B2023,13,12:0
2Converting bacteria into autologous tumor vaccine via surface biomineralization of calcium carbonate for enhanced immunotherapy显示文摘Autologous cancer vaccine that stimulates tumor-specific immune responses for personalized immunotherapy holds great potential for tumor therapy.However,its efficacy is still suboptimal due to the immunosuppressive tumor microenvironment(ITM).Here,we report a new type of bacteria-based autologous cancer vaccine by employing calcium carbonate(CaCO_(3))biomineralized Salmonella(Sal)as an in-situ cancer vaccine producer and systematical ITM regulator.CaCO_(3) can be facilely coated on the Sal surface with calcium ionophore A23187 co-loading,and such biomineralization did not affect the bioactivities of the bacteria.Upon intratumoral accumulation,the CaCO_(3) shell was decomposed at an acidic microenvironment to atenuate tumor acidity,accompanied by the release of Sal and Ca^(2+)/A23187.Specifically,Sal served as a cancer vaccine producer by inducing cancer cells'immunogenic cell death(ICD)and promoting the gap junction formation between tumor cells and dendritic cells(DCs)to promote antigen presentation.Ca^(2+),on the other hand,was intermalized into various types of immune cells with the aid of A23187 and synergized with Sal to systematically regulate the immune system,including DCs maturation,macrophages polarization,and T cells activation.As a result,such bio-vaccine achieved remarkable effcacy against both primary and metastatic tumors by eliciting potent anti-tumor immunity with full biocompatibility.This work demonstrated the potential of bioengineered bacteria as bio-active vaccines for enhanced tumor immunotherapy.Lina Guo Jinsong Ding Wenhu Zhou 2023Acta Pharmaceutica Sinica B2023,13,12:0
3An injectable signal-amplifying device elicits a specific immune response against malignant glioblastoma显示文摘Despite exciting achievements with some malignancies,immunotherapy for hypoimmunogenic cancers,especially glioblastoma(GBM),remains a formidable clinical challenge.Poor immunogenicity and deficient immune infiltrates are two major limitations to an effective cancer-specific immune response.Herein,we propose that an injectable signal-amplifying nanocomposite/hydrogel system consisting of granulocyte-macrophage colony-stimulating factor and imiquimod-loaded antigen-capturing nanoparticles can simultaneously amplify the chemotactic signal of antigen-presenting cells and the'danger'signal of GBM.We demonstrated the feasibility of this strategy in two scenarios of GBM.In the first scenario,we showed that this simultaneous amplification system,in conjunction with local chemotherapy,enhanced both the immunogenicity and immune infiltrates in a recurrent GBM model;thus,ultimately making a cold GBM hot and suppressing postoperative relapse.Encouraged by excellent efficacy,we further exploited this signal-amplifying system to improve the efficiency of vaccine lysate in the treatment of refractory multiple GBM,a disease with limited clinical treatment options.In general,this biomaterial-based immune signal amplification system represents a unique approach to restore GBM-specific immunity and may provide a beneficial preliminary treatment for other clinically refractorymalignancies.Qiujun Qiu Sunhui Chen Huining He Jixiang Chen Xinyi Ding Dongdong Wang Jiangang Yang Pengcheng Guo Yang Li Jisu Kim Jianyong Sheng Chao Gao Bo Yin Shihao Zheng Jianxin Wang 2023Acta Pharmaceutica Sinica B2023,13,12:0
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