BIOMATERIALS
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2024
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IF 12.8
Weihan Zhang,Shijun Yuan,Zipeng Zhang,Shunli Fu,Shujun Liu,Jinhu Liu,Qingping Ma,Zhenxing Xia,Panpan Gu,Shuying Gao,Zhiyue Zhang,Xinke Zhang,Yongjun Liu,Na Zhang
Tumor cells transmit various immunosuppressive signals and induce a dysfunctional state in T cells, which essentially leads to immune escape and tumor progression. However, developing effective strategies to counteract the domestication of T cells by tumor cells remains a challenge. Here, we prepared pH-responsive lipid nanoparticles (NL/PLDs) co-loaded with PCSK9 shRNA, lonidamine (LND), and low-dose doxorubicin (DOX). NL/PLDs can awaken domesticated T cells function by sending pro-activation, pro-recognition, and pro-killing signals by increasing tumor immunogenicity, increasing the expression of major histocompatibility complex I (MHC-I) on tumor cells, and alleviating the suppression effect of tumor-secreted lactic acid (LA) on the T cell effector function, respectively. In melanoma-bearing mice, NL/PLDs effectively relieved tumor immunosuppressive microenvironment (TIME) and enhanced the antitumor immunity mediated by CD8 + T cells. Furthermore, when combined with aPD-1, NL/PLDs demonstrated strong antitumor effects and increased immunotherapeutic efficacy. This regulatory strategy provides new insights for enhancing immunotherapy by regulating tumor immunosuppressive signals and shows significant potential for clinical tumor treatment.
研究领域:
肿瘤学
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免疫学
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纳米技术
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2024
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IF 10.5
Ming Zhao,Chunting He,Xueyun Zheng,Min Jiang,Zhiqiang Xie,Hongjiao Wei,Shujun Zhang,Ying Lin,Jiaheng Zhang,Xun Sun
Vaccines represent one of the most powerful and cost-effective innovations for controlling a wide range of infectious diseases caused by various viruses and bacteria. Unlike mRNA and DNA-based vaccines, subunit vaccines carry no risk of insertional mutagenesis and can be lyophilized for convenient transportation and long-term storage. However, existing adjuvants are often associated with toxic effect and reactogenicity, necessitating expanding the repertoire of adjuvants with better biocompatibility, for instance, designing self-adjuvating polymeric carriers. We herein report a novel subunit vaccine delivery platform constructed via in situ free radical polymerization of C7A (2-(Hexamethyleneimino) ethyl methacrylate) and acrylamide around the surface of individual protein antigens. Using ovalbumin (OVA) as a model antigen, we observed substantial increases in both diameter (∼70 nm) and surface potential (−1.18 mV) following encapsulation, referred to as n( OVA )C7A. C7A's ultra pH sensitivity with a transition pH around 6.9 allows for rapid protonation in acidic environments. This property facilitates crucial processes such as endosomal escape and major histocompatibility complex (MHC)-I-mediated antigen presentation, culminating in the substantial CD8 + T cell activation. Additionally, compared to OVA nanocapsules without the C7A components and native OVA without modifications, we observed heightened B cell activation within the germinal center, along with remarkable increases in serum antibody and cytokine production. It's important to note that mounting evidence suggests that adjuvant effects, particularly its targeted stimulation of type I interferons (IFNs), can contribute to advantageous adaptive immune responses. Beyond its exceptional potency, the nanovaccine also demonstrated robust formation of immune memory and exhibited a favorable biosafety profile. These findings collectively underscore the promising potential of our nanovaccine in the realm of immunotherapy and vaccine development.
研究领域:
免疫学
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疫苗开发
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纳米技术
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
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IF 13.2
Xietao Ye,Yeyang Sun,Lin Yang,Chen Chen,Shihao Li,Shuo Dong,Xiaoying Qin,Xiaoqi Li,Congyan Liu,Jiege Huo,Yuping Liu,Yan Chen
The low infiltration and insufficient tumor recognition of cytotoxic-T-lymphocytes (CTLs) are the two primary reasons for the low objective response rate of programmed death-1 protein (PD-1) inhibitors in treating microsatellite-stable colorectal-cancer (MSS-CRC). Ginsenoside Rg1 (Rg1) and atractylenolide-I (Att) can promote CTLs infiltration and recognition of CTLs by facilitating dendritic cells (DCs) maturation and upregulating tumor MHC-I expression, respectively, and the combination of two drugs is expected to improve the efficacy of PD-1 inhibitors. However, due to their poor water solubility and limited tumor targeting, the intratumoral delivery of both drugs faces challenges. Our previously reported a tumor-apoptotic-body-membrane (Ab) modified zeolitic-imidazolate-framework (ZIF) for co-delivering Rg1 and Att (Ab@Rg1/Att-ZIF). It could be transported by monocytes/macrophages into the deep tumor regions, however, partial formulations would be degraded by intracellular lysosomes. To overcome this, we innovatively incorporated inulin into Ab@Rg1/Att-ZIF, constructing an Ab/In@Rg1/Att-ZIF delivery system. By virtue of the Ab and inulin coating on its surface, the system could be specifically phagocytosed by monocytes/macrophages while maintaining stability in the lysosomal. Furthermore, after being transported to CRC tissues, inulin of the Ab/In@Rg1/Att-ZIF is enzymatically degraded by enzymes secreted by intratumoral bacteria, releasing Rg1 and Att to promote DCs maturation and upregulate tumor MHC-I expression, respectively. Ab/In@Rg1/Att-ZIF significantly inhibits tumor growth by enhancing CTLs infiltration and recognition, synergizing with PD-1 inhibitors to achieve a tumor suppression rate of ≈80 %, which is markedly higher than the combined efficacy of Ab@Rg1/Att-ZIF. This study provides new insights for the immunotherapy of MSS-CRC and the intratumoral co-delivery of drugs.
研究领域:
免疫治疗
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纳米医学
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药物递送
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肿瘤学
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肿瘤微环境
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癌症免疫学
✓ 已验证
产品关联
DOI
高影响因子
ACS Nano
·
2024
·
IF 15.8
Shiji Fang,Liyun Zheng,Gao-Feng Shu,Chen Xiaoxiao,Xiaoju Guo,Yiming Ding,Wenjing Yang,Jiale Chen,Zhongwei Zhao,Jianfei Tu,Minjiang Chen,Jian-Song Ji
Immunotherapy is the most promising systemic therapy for hepatocellular carcinoma. However, the outcome remains poor. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a role in altering cell-surface protein levels, potentially undermining the efficacy of immunotherapy against tumors. This highlights its potential as a target for antitumor therapy. Herein, CaCO3-based nanoparticles coencapsulated with DOX, an immunogenic cell death (ICD) inducer, and evolocumab was developed to enhanced the efficacy of immunotherapy. The obtained DOX/evolocumab-loaded CaCO3 nanoparticle (named DECP) exhibits a good capacity of acid neutralization and causes ICD of cancer cells. In addition, DECP is able to evaluate the cell-surface level of MHC-I, a biomarker that correlates positively with patients’ overall survival. Upon intravenous injection, DECP accumulates within the tumor site, leading to growth inhibition of hepa1-6 bearing subcutaneous tumors. Specifically, DECP treatment causes augmented ratios of matured dendritic cells, tumor-infiltrating CD8+ T cells and natural killing cells, while concurrently depleting Foxp3+ regulatory T cells. Peritumoral delivery of DECP enhances the immune response of distant tumors and exhibits antitumor effects when combined with intravenous αPD-L1 therapy in a bilateral tumor model. This study presents CaCO3-based nanoparticles with multiple immunomodulatory strategies against hepatocellular carcinoma by targeting PCSK9 inhibition and modulating immune homeostasis in the unfavorable TME.
研究领域:
肿瘤学
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免疫学
·
纳米技术
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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