INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2023
·
IF 8.2
Tongyi Shang,Xinying Yu,Yuan Gu,Rong Du,Yanjun Cai,Yuwei Li,Guodong Zheng,Chaoqun Wang,Jian Zhang,Jifang Liu,Shisong Han,Bin Yang
Cancer immunotherapy is the most promising method for tumor therapy in recent years, among which the macrophages play a critical role in the antitumor immune response. However, tumor-associated macrophages (TAMs) usually display the tumor-promoting M2 phenotype rather than the tumor-killing M1 phenotype. Moreover, the over-expressed CD47 on tumor cells severely hinders the function of macrophages by blocking the CD47/SIRPα pathway. Herein, a nano-assembly system of CHTR/siRNA was constructed through the host-guest interaction of a hyperbranched amino-functionalized β-cyclodextrin and immune agonist imiquimod (R848), while CD47 siRNA was loaded inside through electrostatic interaction. The Toll-like receptor (TLR) 7/8 agonist R848 can “re-educate” macrophages from the protumoral M2 phenotype to antitumoral M1 phenotype, while CD47 siRNA can down-regulate the “don't eat me” CD47 signal on the surface of cancer cells and enhance the phagocytosis of cancer cells by macrophages. Through the dual regulation of TAMs, the immunosuppressive tumor microenvironment was relieved, and the host-guest drug-carrying system resulted in synergistic immunotherapy effect on tumors and inhibited tumor growth. The facile self-assembly of nanodrug offers a new strategy in co-delivery of multiple therapeutic agents for cascade cancer immunotherapy.
研究领域:
肿瘤学
·
免疫学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nano Today
·
2024
·
IF 13.2
Xitong Ren,Haochen Yao,Jiali Sun,Fuxin Xue,Linjie Cui,Yajun Xu,Kazuo Sakurai,Na Shen,Zhaohui Tang
Immune checkpoint blockade (ICB) therapy represents a promising approach widely embraced for its sustained efficacy upon activation of the body’s immune responses. Nonetheless, its effectiveness exhibits significant variability among patients, with a response rate below 30 %. A key limitation is the insufficient tumor infiltration and specific priming of CD8 + T cells. To address this, we develop ROS-responsive TLR7/8 nanoagonists {methoxy poly(ethylene glycol)- b -poly-[(N-2-hydroxyethyl)-aspartamide]- g -thioketal-R848}, designated as R848 NPs, wherein the C-4 amino of R848 is chemically blocked to enable selective release under endogenous tumor ROS conditions, thereby mitigating the severe systemic cytokine storms associated with R848. Additionally, ultrasound (US) is employed to induce immune cell death and facilitate intratumoral enrichment of R848 NPs. The proposed combination treatment, R848 NPs+US, effectively enhances antigen presentation by dendritic cells (DCs), facilitates intratumoral distribution of active R848, mitigates systemic inflammatory responses, promotes the release of damage-associated molecular patterns, and upregulates the expression of costimulatory molecules on DCs. Ultimately, R848 NPs+US plays a crucial role in bolstering CD8 + T cells immunity, synergizing with αPDL1 for CT26 tumor suppression (rate: 99.0 %, Q value: 1.68), eliciting memory immunity, and preventing tumor rechallenge. This work provides a novel strategy to potentiate the cancer immunity and a guidance for ICB therapy.
研究领域:
癌症免疫疗法
·
纳米技术
·
免疫学
·
肿瘤学
✓ 已验证
产品关联
DOI
高影响因子
Polymers
·
2022
·Vol. 14
·期 24
·5466
·
IF 4.967
Changcai Teng,Xiongyan Meng,Yeqin Hu,Hongzhao Mao,Huiting Li,Jing Yang,Tiantian Sun,Shuai Meng,Chengli Zong
Small synthetic TLR7/8-agonists can be used as vaccine adjuvants to enhance cell and humoral-mediated immune responses to specific antigens. Despite their potency, after local injection they can be dispersed to undesired body parts causing high reactogenicity, limiting their clinical applications. Here we describe a vaccination strategy that employs the covalent conjugate of a mannose and TLR7/8 agonist as a vaccine adjuvant to take advantage of mannose binding C-type lectins on dendritic cells to enhance the vaccine’s immunogenicity. The mannose-TLR7/8 agonist conjugate can self-assemble into nanoparticles with the hydrophilic mannose on the outside and hydrophobic TLR7/8 agonist inside. Although its ability to stimulate HEK-BlueTMhTLR7/8 cells dropped, it can efficiently stimulate mouse bone marrow-derived dendritic cells as indicated by the up-regulation of CD80 and CD86, and higher cytokine expression levels of TNF-α, IL6, and IL-12p70 than the native TLR7/8 agonist. In vivo, vaccination using the SARS-CoV-2 RBD trimer as the antigen and the conjugate as the adjuvant induced a significantly higher amount of IgG2a. These results suggest that the mannose-TLR7/8-agonist conjugate can be used as an effective vaccine adjuvant.Keywords:adjuvants;mannose;TLR7/8 agonist;immune responses;cytokines;antibody
研究领域:
免疫学
·
病毒学
·
药学
✓ 已验证
DOI
PubMed
高影响因子
Biomaterials Science
·
2025
·
IF 5.7
Chuwen Luo,Chaoying Kong,Yuxiao Zhang,Yajun Xu,Zhaohui Tang
Systemic immunotoxicity caused by off-target activation is still a critical obstacle to clinical translation of imidazoquinoline (IMDQ) drugs, a kind of TLR7/8 agonists. Here, we present an ultrasound-responsive, azide-modified IMDQ nano-prodrug (IMDQ-N3 NPs) that enables spatiotemporally controlled activation through ultrasound, improving the selectivity and safety. Concomitantly, riboflavin-based sonosensitizers were co-delivery to these nanoparticles, increasing their local concentration surrounding the prodrug, achieving a 12.2-fold enhancement in the ultrasonic reduction rate of IMDQ-N3. In murine models, IMDQ-N3 NPs demonstrated no weight loss and negligible systemic inflammatory factor elevation relative to equivalent-dose unmodified IMDQ. Combined with ultrasound irradiation, IMDQ-N3 NPs demonstrated 35.2-fold higher tumor distribution of active drug compared to non-irradiated free IMDQ-N3, achieving 95.7% tumor suppression and 60% long-term survival. Flow cytometry analysis revealed enhanced dendritic cell maturation, cytotoxic T-cell infiltration, and durable immune memory. This work establishes a generalizable platform for precision delivery of immunostimulatory agents, addressing key translational challenges in cancer immunotherapy.
研究领域:
癌症免疫治疗
·
纳米医学
·
药物递送
·
生物工程
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nano Research
·
2021
·Vol. 15
·期 1
·510-518
·
IF 8.897
Wu Jia-Si,Li Jia-Xian,Shu Na,Duan Qi-Jia,Tong Qi-Song,Zhang Jing-Yang,Huang Yong-Cong,Yang Si-Yu,Zhao Zhi-Bin,Du Jin-Zhi
Tumor associated macrophages (TAMs) tend to exhibit tumor-promoting M2 phenotype and contribute to the development of immunosuppressive microenvironment of solid tumors. Reprograming TAMs from M2 into tumoricidal M1 phenotype is robust for stimulating tumor immunosuppressive microenvironment (TIME). In this study, we developed a poly(amidoamine) (PAMAM) derivative dendrimer (denoted as fourth generation- N,N -diethylaminoethyl (G4-DEEA)) for efficient loading of Toll-like receptor 7 and 8 (TLR7/8) agonist (R848) to remodel the TIME for potent cancer immunotherapy. G4-DEEA exhibited a high loading capacity of R848 up to 35.9 wt% by taking advantage of its dendritic structure. The resulting formulation (designated as G4-DEEA@R848) effectively polarized M2 macrophages into M1 phenotype in vitro , and improved the maturation and activation of antigen-presenting cells. In the 4T1 orthotopic breast cancer model, G4-DEEA@R848 showed a stronger tumor inhibitory effect than free drug. The mechanistic studies suggested that G4-DEEA@R848 could significantly stimulate the TIME by repolarizing TAMs into M1 phenotype, reducing the presence of immunosuppressive myeloid cells and increasing the infiltration of tumor cytotoxic T cells. This study provides a simple but effective dendrimer-based strategy to improve the formulation of R848 for improved cancer immunotherapy.
研究领域:
癌症免疫治疗
·
药学
·
免疫学
✓ 已验证
产品关联
DOI
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Ying Xu,Jing Yang,Xiongyan Meng,Shuai Meng,Tiantian Sun,Ning Ding,Chengli Zong
Covalently linking an adjuvant to an antigenic protein enhances its immunogenicity by ensuring a synergistic delivery to the immune system, fostering a more robust and targeted immune response. Most adjuvant-protein conjugate vaccines incorporate only one adjuvant due to the difficulties in its synthesis. However, there is a growing interest in developing vaccines with multiple adjuvants designed to elicit a more robust and targeted immune response by engaging different aspects of the immune system for complex diseases where traditional vaccines fall short. Here, we pioneer the synthesis of a dual-adjuvants protein conjugate Vaccine 1 by assembling a toll-like receptor 7/8 (TLR7/8) agonist, an invariant natural killer T cell (iNKT) agonist with a clickable bicyclononyne (BCN). The BCN group can bio-orthogonally react with azide-modified severe acute respiratory syndrome coronavirus-2 receptor-binding domain (SARS-CoV-2 RBD) trimer antigen to give the three-component Vaccine 1 . Notably, with a mere 3 μg antigen, it elicited a balanced subclass of IgG titers and 20-fold more IgG2a than control vaccines, highlighting its potential for enhancing antibody-dependent cellular cytotoxicity. This strategy provides a practicable way to synthesize covalently linked dual immunostimulants. It expands the fully synthetic self-adjuvant protein vaccine that uses a single adjuvant to include two different types of adjuvants.
研究领域:
免疫学
·
病毒学
·
药物化学
·
疫苗研发
✓ 已验证
DOI
高影响因子
Advanced Healthcare Materials
·
2022
·Vol. 11
·期 12
·2102781
·
IF 11.092
Yutong Liu,Hui Li,Huajun Zhao,Yanyun Hao,Simon Van Herck,Zejun Xu,Guan Wang,Xiao Wang,Xinke Zhang,Xiaoyan Ge,Xia Li,Ailu Yang,Hongfei Chen,Jing Zou,Wentao Wang,Bruno G. De Geest,Zhiyue Zhang
In situ anti-tumor vaccination is an attractive type of cancer immunotherapy which relies on the effectiveness of dendritic cells (DCs) to engulf tumor antigens, become activated, and present antigens to T cells in lymphoid tissue. Here, a multifunctional nanocomplex based on calcium crosslinked polyaspartic acid conjugated to either a toll-like receptor (TLR)7/8 agonist or a photosensitizer is reported. Intratumoral administration of the nanocomplex followed by laser irradiation induces cell killing and hence generation of a pool of tumor-associated antigens, with concomitant promotion of DCs maturation and expansion of T cells in tumor-draining lymph nodes. Suppression of tumor growth is observed both at the primary site and at the distal site, thereby hinting at successful induction of an adaptive anti-tumor response. This strategy holds promise for therapeutic application in a pre-operative and post-operative setting to leverage to mutanome of the patient's own tumor to mount immunological memory to clear residual tumor cells and metastasis.
研究领域:
癌症免疫疗法
·
纳米技术
·
免疫学
·
肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2025
·
IF 5.7
Jia-Qi Luo,Yong-Cong Huang,Jing-Yang Zhang,Qi-Song Tong,Areesha Batool,Jinzhi Du,Yuyou Duan
Antigen-presenting cells (APCs), such as macrophages and dendritic cells (DCs) are key players in modulating the immune responses of cytotoxic T lymphocytes (CTLs). Resiquimod (R848), a toll-like receptor (TLR) agonist, has demonstrated the capacity to enhance APC function and reprogram the phenotype of macrophages; however, the unfavorable in vivo performance constrains its therapeutic potential. Here, we developed R848-loaded mesoporous silica nanoparticles (denoted as R848@MSN-bi-PEG) with pH-responsive surface PEG detachment to effectively modulate APCs. The acidic tumor pH triggered PEG detachment when R848@MSN-bi-PEG accumulated at the tumor site, thereby promoting APC uptake and R848 release, which facilitated DCs maturation and macrophage repolarization to a pro-inflammatory phenotype. The in vivo antitumor study indicated that R848@MSN-bi-PEG led to potent anti-tumor immunity by modulating the immunosuppressive tumor microenvironment. This approach offers a novel strategy to improve the effectiveness of cancer immunotherapy.
研究领域:
生物医学工程
·
免疫学
·
肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2025
·
IF 16
Mengyao Ma,Ximu Li,Mingyuan Zhong,Xuejing Li,Jiang Yu,Zhaomeng Wang,Qingzhi Lv,Xin Li,Zhonggui He,Hongzhuo Liu,Yongjun Wang
Cancer vaccines, a critical technology in cancer immunotherapy, have shown great therapeutic potential. However, traditional vaccines based on tumor cell lysates (TCLs) have shown disappointing results in early clinical trials due to low immunogenicity, in vivo instability, and the inability to codeliver with adjuvants. To address these issues, we developed a nanoparticle vaccine, R848-GA@TCLs, by modifying the toll-like receptor 7/8 (TLR7/8) agonist R848 with gallic acid. This nanovaccine leverages the “capturing” ability of the galloyl moiety to coload TCLs and R848, forming stable nanoparticles. R848-GA@TCLs efficiently target lymph nodes, increasing TCL accumulation 10-fold, and enable the synchronized release of antigens and adjuvants within dendritic cells (DCs). Our results show that R848-GA@TCLs increase with respect to the cross-presentation of tumor antigens, promote the production of pro-inflammatory cytokines, and activate DCs, leading to a significant increase in effector T cells, natural killer (NK) cells, and M1 macrophages. This strong immune response resulted in potent antitumor effects, with R848-GA@TCLs demonstrating efficacy in multiple tumor models by significantly inhibiting tumor growth and metastasis. In conclusion, R848-GA@TCLs represent a personalized cancer vaccine capable of codelivering TCLs and adjuvants, eliciting robust antitumor immune responses, and hold great potential for clinical applications.
研究领域:
肿瘤学
·
免疫学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2026
·
IF 17.3
Yuan Gao,Shiyu Yuan,Jiaqi Zhang,Fangming Liang,Yue Wang,Yinan Song,Ning Li,Zhaochu Xu,Yan Zhao,Yongjun Wang,Hongzhuo Liu
In situ cancer vaccination is limited when antigens diffuse or degrade, adjuvants act systemically, and the timing of immune licensing is misaligned. Here, we report a penetrate-then-gate design that decouples distribution from activation. Complementary, clickable poly(propylene sulfide) (PPS) nanoparticles (∼25 nm) first penetrated the tumor parenchyma after intravenous administration. Brief near-infrared irradiation then gated intracellular ROS generation by a photosensitizer (PPa), oxidizing PPS to poly(propylene sulfone) (PPSU), exposing azide/DBCO handles, and driving in situ assembly. The resulting PPSU network captured endogenous antigens, thereby colocalizing antigen availability with TLR7/8 agonist (IMDQ). In mice, optical imaging indicated earlier and sustained intratumorally exposure at irradiation for coadministration (the two formulations premixed before injection) versus sequential dosing (PPa-PPSN3 first, followed by IMDQ-PPSDBCO before irradiation), aligning exposure with the licensing window. Across multiple cancer models, coadministration improved primary control, elicited rechallenge protection, and suppressed distant growth, with restrained systemic cytokines. This work applies a spatiotemporal alignment principle for in situ vaccination to achieve precise and durable tumor immunotherapy in a modular way.
✓ 已验证
DOI
PubMed
高影响因子
ADVANCED MATERIALS
·
2024
·
IF 27.4
Ruonan Wang,Huixin Li,Shasha He,Yuanji Feng,Cong Liu,Kai Hao,Danhua Zhou,Xiaoyuan Chen,Huayu Tian
Lymph nodes are crucial immune foci as the primary target for cancer immunotherapy. However, the anti-tumor functions of tumor-draining lymph nodes (TDLNs) are critically suppressed by tumors. Here, a novel spatiotemporal nano-regulator is presented, designed to modulate the dendritic cells (DCs) in TDLNs, establishing a supportive niche for immune surveillance. The DC-mediated nano-regulator (DNR) is established by the self-assembly of an imidazoquinoline (IMDQ) prodrug, inhibitory immune checkpoint (ICP) siRNA, and mannan (a TLR4 agonist). This unique design leverages the spatiotemporal activation of TLR4 and TLR7/8, thereby optimizing DC maturation and cytokine production. This further promotes efficient T cell priming. Simultaneously, the ICP-targeting siRNA mitigates the tolerogenic effects induced by tumor-derived factors and TLR activation, preventing T cell exhaustion. In essence, DNR facilitates potent remodeling of TDLNs and the tumor microenvironment, activating the anti-tumor immunity cascade. When combined with vaccines, DNR greatly promotes tumor regression and the establishment of long-term immunological memory.
研究领域:
癌症免疫疗法
·
免疫学
·
纳米医学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2025
·
IF 12.5
Liubing Li,Zenghui Gu,Yanxian Wu,Subin Lin,Xiaju Cheng,Leshuai W. Zhang,Jianzhong Qin,Qirong Dong,Yong Wang,Yangyun Wang
Combining radiotherapy with immunotherapy holds promise for treating solid tumors and metastases, but challenges persist, including hypoxia-induced immunosuppression and immune-related adverse events from off-target toxicity. To address this, we engineered an in-situ formed hydrogel by crosslinking hyaluronic acid and polyvinyl alcohol with a reactive oxygen species (ROS)-responsive linker (3-aminophenylboronic acid). This hydrogel leverages radiotherapy-induced ROS within the tumor microenvironment to trigger localized release of nitric oxide (NO) and the toll-like receptor 7/8 (TLR7/8) agonist R848. NO normalizes hypoxic tumor vasculature, while R848 amplifies radiotherapy-initiated antitumor immunity. In breast cancer and bone metastasis models, this radioimmune-regulated hydrogel significantly enhanced tumor normoxia, promoted dendritic cell maturation, and primed CD8 + T cells, substantially improving the efficacy of combined radioimmunotherapy. Our study highlights a potent hydrogel-based strategy to overcome key limitations in advanced cancer therapy.
研究领域:
肿瘤学
·
生物材料
·
免疫治疗
·
放射治疗
·
纳米医学
·
药学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）