Acta Biomaterialia
·
2022
·
IF 10.633
Afeng Yang,Shupei Sheng,Yun Bai,Guozheng Xing,Xuya Yu,Dunwan Zhu,Lin Mei,Xia Dong,Feng Lv
Vascular abnormalities are directly related to the tumor immunosuppressive microenvironment, which is an important obstacle to effective immunotherapy. The combination of antiangiogenesis therapy and immunotherapy may promote a mutually reinforcing cycle of immune reprogramming and vascular normalization to increase the effectiveness of immunotherapy. Herein, a hydrogel/nanosystem-mediated antiangiogenesis combined immunotherapy strategy was used to regulate the tumor microenvironment by the controlled release of apatinib, CD47 antibody (aCD47), and CpG. The combination of hydrogel with nanoparticles protected drug activity and maintained a long-term slow release of the drug for maximum synergistic efficacy. Apatinib promotes vascular normalization in tumors and enhances the efficacy of aCD47-based immunotherapy. The addition of immunoadjuvant CpG further enhanced antigen presentation and stimulated the anti-tumor activity of macrophages to strengthen the efficacy of antiangiogenesis combined immunotherapy. The main effector immune cells , including CD4 + T , CD8 + T , NK, and activity DCs, were significantly increased after combination treatment, while the proportion of various immunosuppressive cells decreased significantly, especially MDSCs and M2-polarized macrophages. Based on an effective systemic immune response, the hydrogel/nanoparticle-mediated cooperative combination of antiangiogenesis and immunotherapy enhanced the synergistic effect for primary tumors and prevented metastasis for tumor treatment. The biomaterial-mediated antiangiogenesis combined immunotherapy strategy is a promising strategy for effective immunotherapy. Statement of significance Relieving immunosuppression of the tumor microenvironment is the key to restoring and rebuilding the normal anti-tumor immune defense of the body. Vascular abnormalities are directly related to the tumor immunosuppressive microenvironment, which is an important obstacle to effective immunotherapy. The combination of antiangiogenesis and immunotherapy may promote a mutually reinforcing cycle of immune reprogramming and vascular normalization to increase the effectiveness of immunotherapy. For the combination of antiangiogenesis and immunotherapy, effective drug delivery to overcome local immune tolerance and regulate the tumor microenvironment to increase therapeutic effects is an important issue. The hydrogel/nanomaterial composite system constructs a dual sustained-release system to achieve step-by-step controlled release of antiangiogenic drugs and immune immunotherapy drugs to promote cooperative combination therapy.
研究领域:
肿瘤学
·
药学
·
纳米技术
·
免疫学
·
药物递送系统
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2022
·Vol. 20
·期 1
·1-22
·
IF 9.429
Sha Xuan,Dai Yue,Chong Lijuan,Wei Min,Xing Mengyuan,Zhang Chun,Li Jingjing
Macrophages participate in many links in the pathological process of atherosclerosis (AS) and the regulation of influence of macrophages at the molecular level might be a new avenue for AS treatment. For this aim, the macrophage membrane biomimetic nanoparticles, derived from macrophage membrane coated SHP1i-loaded liposome NPs (MM@Lips-SHP1i) was designed. Due to the reservation of intrinsic membrane proteins and function from macrophages, the biomimic nanoparticles could effectively evade clearance by the immune system, prolong blood circulation time and actively tend and aggregate to atherosclerotic plaques. More importantly, in the plaque area, MM@Lips-SHP1i nanoparticles could compete with macrophages in vivo to bind with oxidized low-density lipoprotein (oxLDL) and lipopolysaccharide (LPS), reduce uptake of new lipids by macrophages, reduce foam cell formation, and inhibit the expression of pro-inflammatory cytokines. In addition, small molecule inhibitor of SHP-1, the downstream effector molecule of CD47 loaded in macrophage membrane biomimetic nanoparticles could interrupt CD47-SIRPα signal transduction in monocytes and macrophages, thereby enhancing the efferocytosis of macrophages, inhibiting the progression of plaque, achieving synergistic treatment of atherosclerosis. This work focuses on the key process in the formation of AS, macrophage foaming and chronic inflammation, and is based on the fact that macrophage membrane biomimetic nanoparticles can preserve the key surface proteins of macrophages closely related to the formation of AS, providing a new avenue to inhibit the progression of AS by utilizing the biological characteristics of macrophage membrane in macrophage membrane biomimetic nanoparticles.
研究领域:
纳米技术
·
药理学
·
心血管疾病
·
免疫学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Small
·
2020
·Vol. 16
·期 46
·2004240
·
IF 11.459
Ya-Ru Zhang,Jia-Qi Luo,Jing-Yang Zhang,Wei-Min Miao,Jia-Si Wu,Hua Huang,Qi-Song Tong,Song Shen,Kam W. Leong,Jin-Zhi Du,Jun Wang
Activation of the phagocytosis of macrophages to tumor cells is an attractive strategy for cancer immunotherapy, but the effectiveness is limited by the fact that many tumor cells express an increased level of anti-phagocytic signals (e.g., CD47 molecules) on their surface. To promote phagocytosis of macrophages, a pro-phagocytic nanoparticle (SNPA CALR&aCD47 ) that concurrently carries CD47 antibody (aCD47) and a pro-phagocytic molecule calreticulin (CALR) is constructed to simultaneously modulate the phagocytic signals of macrophages. SNPA CALR&aCD47 can achieve targeted delivery to tumor cells by specifically binding to the cell-surface CD47 and block the CD47-SIRPα pathway to inhibit the “don't eat me” signal. Tumor cell-targeted delivery increases the exposure of recombinant CALR on the cell surface and stimulates an “eat me” signal. Simultaneous modulation of the two signals enhances the phagocytosis of 4T1 tumor cells by macrophages, which leads to significantly improved anti-tumor efficacy in vivo. The findings demonstrate that the concurrent blockade of anti-phagocytic signals and activation of pro-phagocytic signals can be effective in macrophage-mediated cancer immunotherapy.
研究领域:
癌症免疫学
·
纳米技术
·
免疫疗法
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2023
·
IF 9.5
Cui Tang,Hui Wang,Lina Guo,Chan Zou,Jianming Hu,Hanyong Zhang,Wenhu Zhou,Guoping Yang
Atherosclerosis (AS) is a major contributor to cardiovascular diseases, necessitating the development of novel therapeutic strategies to alleviate plaque burden. Macrophage efferocytosis, the process by which macrophages clear apoptotic and foam cells, plays a crucial role in plaque regression. However, this process is impaired in AS lesions due to the overexpression of CD47, which produces a “do not eat me” signal. In this study, we investigated the potential of CpG, a toll-like receptor 9 agonist, to enhance macrophage efferocytosis for AS therapy. We demonstrated that CpG treatment promoted the engulfment of CD47-positive apoptotic cells and foam cells by macrophages. Mechanistically, CpG induced a metabolic shift in macrophages characterized by enhanced fatty acid oxidation and de novo lipid biosynthesis, contributing to its pro-efferocytic effect. To enable in vivo application, we conjugated CpG on silver nanoparticles (AgNPs) to form CpG-AgNPs, which could protect CpG from biological degradation, promote its cellular uptake, and release CpG in response to intracellular glutathione. Combining the intrinsic antioxidative and anti-inflammatory abilities of AgNPs, such nanomedicine displayed multifunctionalities to simultaneously promote macrophage efferocytosis and repolarization. In an ApoE–/– mouse model, intravenous administration of CpG-AgNPs effectively targeted atherosclerotic plaques and exhibited potent therapeutic efficacy with excellent biocompatibility. Our study provides valuable insights into CpG-induced macrophage efferocytosis and highlights the potential of CpG-AgNPs as a promising therapeutic strategy for AS.
研究领域:
纳米医学
·
心血管疾病
·
免疫学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Regenerative Biomaterials
·
2024
·
IF 5.6
Li Bingyi,He Mei,Xu Zichen,Zhang Qianting,Zhang Liyuan,Zhao Shuang,Cao Yu,Mou Nianlian,Wang Yi,Wang Guixue
Atherosclerosis (AS), an inflammatory disease characterized by lipid accumulation, has a high global incidence and mortality rate. Recently, nanotherapeutic approaches that target pathological sites and improve drug bioavailability and biocompatibility hold great promise for AS treatment. In this study, a biomimetic ROS-responsive hyaluronic acid–based nanomaterial was prepared for targeted anti-AS. Specifically, a safe ROS-responsive carrier based on hyaluronic acid (HSP) was prepared to load methotrexate (MTX), a drug known for its ability to enhance lipid excretion, resulting in the formation of MTX-loaded nanoparticles (MTXNPs). Furthermore, the macrophage membrane was coated on the surface of MTXNPs to obtain MM/MTXNPs. Both MTXNPs and MM/MTXNPs exhibited ROS responsiveness and demonstrated excellent biocompatibility. In vitro experiments revealed that MM/MTXNPs could evade macrophage phagocytosis and exhibited high uptake rates by inflamed endothelial cells. MM/MTXNPs also reduced lipid accumulation in foam cells. In vivo experiments showed that MM/MTXNPs exhibited superior accumulation at AS plaque sites, facilitated by the surface membrane layer containing integrin α4β1 and CD47, resulting in an enhanced therapeutic effect in inhibiting plaque development compared to free MTX and MTXNPs. Therefore, HSP represents a promising nanocarrier to load hydrophobic MTX, enabling effective and biocompatible enhancement of AS treatment.
研究领域:
纳米医学
·
药学
·
生物医学工程
·
心血管疾病
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2018
·
IF 8.806
Zhenqi Jiang,Yuchen Tian,Dingying Shan,Yinjie Wang,Ethan Gerhard,Jianbi Xia,Rong Huang,Yan He,Aiguo Li,Jianchao Tang,Huimin Ruan,Yong Li,Juan Li,Jian Yang,Aiguo Wu
Nanoparticle-based tumor therapies are extensively studied; however, few are capable of improving patient survival time due to premature drug leakage, off target effects, and poor tissue penetration. Previously, we successfully synthesized a novel family of Y 1 receptor (Y 1 R) ligand modified, photoluminescent BPLP nanobubbles and nanoparticles for targeted breast cancer ultrasound imaging ; however, increased accumulation could also be observed in the liver, kidney, and spleen, suggesting significant interaction of the particles with macrophages in vivo . Herein, for the first time, we imparted antiphagocytosis capability to Y 1 R ligand functionalized BPLP-WPU polymeric micelles through the incorporation of a CD47 human glycoprotein based self-peptide. Application of self-peptide modified, DOX loaded micelles in vivo resulted in a 100% survival rate and complete tumor necrosis over 100 days of treatment. In vivo imaging of SPION loaded, self-peptide modified micelles revealed effective targeting to the tumor site while analysis of iron content demonstrated reduced particle accumulation in the liver and kidney, demonstrating reduced macrophage interaction, as well as a 2-fold increase of particles in the tumor. As these results demonstrate, Y 1 R ligand, self-peptide modified BPLP-WPU micelles are capable of target specific cancer treatment and imaging, making them ideal candidates to improve survival rate and tumor reduction clinically.
研究领域:
癌症治疗
·
纳米医学
·
药理学
·
分子影像
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Sufen Li,Jingyan Zhang,Tong Yu,Guangtao Song,Jia Ke,Kai Wang,Yichong Xu,Yiling Hong,Tingting Meng,Yun Hong,Hong Yuan,Fuqiang Hu
Glioblastoma-associated macrophages & microglia (GAMs) are critical immune cells within the glioblastoma (GBM) microenvironment. Their phagocytosis of GBM cells is crucial for initiating both innate and adaptive immune responses. GBM cells evade this immune attack by upregulating the anti-phagocytic molecule CD47 on their surface. Although CD47 knockdown has shown promise in reducing tumor volume and increasing survival in GBM models, the efficacy of anti-CD47 antibodies remains limited clinically, partly due to the blood-brain tumor barrier (BBTB) and the insufficient pro-phagocytosis efficacy of CD47 blockade alone. Here, we introduce CSSOssMIT@MM-PEP 20 , a PEP 20 -linked microglia membrane (MM) camouflaged CSSOssMIT prodrug micelle. The MM targets vascular cell adhesion molecule-1 on the BBTB and enhances the penetration of CSSOssMIT@MM-PEP 20 into the GBM tissue. CSSOssMIT@MM-PEP 20 disassembles into MM-PEP 20 and CSSOssMIT through the proton sponge effect in the acidic microenvironment. MM-PEP 20 blocks the CD47-SIRPα axis, disabling the ‘don't eat me’ signal, while CSSOssMIT releases MIT within tumor cells to promote immunogenic cell death and amplify the ‘eat me’ signal. In an orthotopic GBM mouse model, CSSOssMIT@MM-PEP 20 increased GAMs-mediated phagocytosis of GBM cells by 5.01-fold and enhanced CD8 + T cell infiltration by 8.63-fold, demonstrating significant GBM inhibition. Overall, this study presents a noninvasive strategy to traverse the BBTB and modulate GAMs phagocytosis, thereby facilitating effective anti-GBM chemo-immunotherapy.
研究领域:
肿瘤学
·
神经科学
·
药理学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nano Today
·
2024
·
IF 13.2
Yanjie Han,Haifeng Lu,Zikuan Gu,Peixin Guan,Zhen Liu
In situ reprogramming of tumor associated macrophages (TAMs) to resurge their phagocytic ability holds great potential in cancer treatment. However, most of currently existing TAMs-reshaping approaches fail to effectively reprogram TAMs due to low efficiency, poor specificity, and potential immune side effects. Herein, we report a strategy called molecularly imprinted lysosomal nanodegrader (MILND) for resurging the phagocytosis of macrophages and reversing the "don't eat me" CD47-SIRPα signal via degrading SIRPα in lysosomes. The MILND, which was rationally engineered by controllable molecular imprinting using the N-terminal epitope of SIRPα as template, could specifically bind SIPRα on TAMs. Upon being engulfed by TAMs via endocytosis, the MILND-SIRPα complex was transferred to lysosomes for degradation. The degradation of SIRPα induced a cascade reaction of the downstream PI3K signaling pathway to resurging the phagocytic and recognition capability of TAMs towards cancer cells. Ultimately, MILND resulted in a subsequent series of anti-tumor effects. Benefiting from this, MILND effectively sensitized the immune microenvironment and amplified CD8+ T cell responses, leading to substantial tumor growth inhibition in tumor-bearing mouse model. Thus, this work provides an efficient and versatile immunomodulatory strategy for enhanced antitumor immunotherapy.
研究领域:
癌症生物学
·
免疫治疗
·
纳米技术
·
细胞信号传导
✓ 已验证
产品关联
DOI
高影响因子
COMPOSITES PART B-ENGINEERING
·
2022
·
IF 11.322
Yonghong Fan,Juan Pei,Xinxin Li,Yinhua Qin,Youqian Xu,Ming Ke,Jie Zhang,Yong Liu,Ju Tan,Mingcan Yang,Gang Li,Tianqing Li,Chuhong Zhu
Tissue-engineered vascular grafts (TEVGs) show great potential in clinics for treating vascular diseases. However, the complications including thrombosis, delayed endothelialization , and endothelial-to-mesenchymal transition (EndMT) induced pathological remodeling have been demonstrated to be the main cause of graft failure. Here, we have developed a multifunctional surface by immobilizing ALK5 inhibitor loaded covalent organic framework (COF) nanoparticles , recombinant CD47 protein, and vascular endothelial growth factor (VEGF). Such a surface can prevent thrombosis and stenosis in TEVGs. Immobilization of VEGF facilitated the recruitment of endothelial-forming cells to accelerate endothelialization. Grafting of CD47 endowed the TEVGs with stealth function to inhibit the adhesion and activation of platelets and macrophages, thereby suppressing thrombus formation and reducing the secretion of EndMT triggers (i.e. TNF-α and IL-1β). In addition, long-term in situ delivery of ALK5 inhibitor could block the TGF-β signaling pathway that mediated EndMT to prevent intima hyperplasia and endothelial dysfunction during graft remolding. This synergistic strategy is competent to support the formation of functional endothelium on the neo-intima, and has shown promising preliminary results in keeping the patency of TEVGs.
研究领域:
组织工程
·
血管生物学
·
生物材料
·
免疫学
·
分子生物学
✓ 已验证
产品关联
DOI
高影响因子
Nano-Micro Letters
·
2021
·Vol. 14
·期 1
·1-21
·
IF 16.419
Zhang Xiaoge,Cheng Lili,Lu Yao,Tang Junjie,Lv Qijun,Chen Xiaomei,Chen You,Liu Jie
Gene-engineering tumor cell membrane with CD47 over-expression is achieved to improve the macrophage-mediated phagocytosis of tumor cells by blocking CD47 immune checkpoint.
A cascade-enzyme nanoreactor combining tumor enzyme dynamic therapy, phototherapy, and deoxygenation-activated chemotherapy is proposed.
Glucose oxidase and chloroperoxidase can generate sufficient HClO to kill normoxic tumor cells, and tirapazamine can be subsequently activated to kill hypoxic tumor cells.
研究领域:
纳米技术
·
癌症治疗
·
生物医学工程
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2022
·
IF 11.467
Jiahui Zou,Jianhua He,Xiaobo Wang,Yajie Wang,Chenchen Wu,Mengya Shi,Hulin Jiang,Zimei Wu,Jianping Liu,Wenli Zhang
Despite the tremendous theranostics potential of nano-scale drug delivery system (NDDS) in oncology field, their tumor-targeting efficiency and safety remain major challenges due to their proneness of off-target accumulation through widespread vascular endothelial gaps (up to 1 μm). To address this problem, in this research, micro-sized cellular platelet “ghosts” (PGs, 1.32 μm, platelet without inner granules and coagulation) were employed as carriers to ship hollow gold nanoparticles (HGNs, 58.7 nm), forming a hierarchical biosafe system ( [email protected] ) to reduce normal tissue interception and enhance tumor targeting delivery of HGNs for improved photothermal therapy . PGs were prepared by an optimized “swelling-extrusion-elution” method, HGNs were loaded in PGs ( [email protected] ) through a “hypotonic dialysis” method and the safety and biodistribution of the system was evaluated in vitro and in vivo . In in vitro condition that stimulated the tumoral vessel acidic microenvironment (pH = 6.5), [email protected] were demonstrated with enhanced membrane fluidity through down-regulation of the glycoprotein Ib expressed on the PGs. This change induced a burst release of nano-sized HGNs which were capable to traverse vascular endothelium layer on a tumor-endothelial cell transwell model, whilst the micro-sized PG carriers were intercepted. In comparison to nano-sized platelet membrane-coated carriers ( [email protected] ), [email protected] showed enhanced internalization and cytotoxicity to 4T1 cells. In animal models, [email protected] remarkably prolonged circulation most likely due to the presence of “self-recognition” receptor-CD47 of PGs, and effectively reduced normal tissue interception via the micro-scale size effect. These both contributed to the significantly improved tumor targeting efficiency of HGNs. [email protected] generated the greater antitumor photothermal efficacy alongside safety in the animals compared to [email protected] Collectively, this study demonstrated the potential of the micro-scale PGs equipped with adjusted membrane GP Ib as biosafe vehicles for HGNs or possibly other nanodrugs. The statement of significance Despite the tremendous theranostics potentials, the safety and tumor-targeting efficiency of nano-scale drug delivery systems (NDDS) are compromised by their undesirable accumulation in normal tissues with widespread vascular endothelial gaps, such as many tumor-targeted NDDSs still accumulated much in liver and/or spleen. Herein, we explored a micro-nano biomimetic cascade delivery system to address the above drawbacks. By forming a hierarchical biosafe system, micro-sized platelet “ghost” (PGs, 1.32 μm) was employed as tumor-targeted delivery carrier to transport hollow gold nanoparticles (HGNs, 58.7 nm). It was demonstrated that this micro-size system could maintain platelet membrane structure thus prolong in vivo circulation, while avoiding extravasation into normal tissues. [email protected] could sensitively respond to the acidic microenvironment near tumor vessel via down-regulation of glycoprotein Ib and rapidly release “nano-bullets”-HGNs to further penetrate into the tumor tissues through EPR effect , thus enhancing photothermal efficacy generated by HGNs under NIR irradiation. Collectively, the micro-scaled PGs could be biosafe vehicles for improved tumor-targeted delivery of HGNs or possibly other nanodrugs.
研究领域:
肿瘤学
·
纳米技术
·
药物递送
·
生物医学工程
·
治疗诊断学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6.8
Yan Chen,Ming Zhang,Yanqin He,Suying Li,Shuaiqi Feng,Zhifang Liu,Ning Zhang,Meifeng Liu,Qingpeng Wang
Epithelial–mesenchymal transition (EMT) is a critical process for cancer progression, which is crucial in inhibiting the immunity in tumors and further boosting tumor metastasis. The suppression of EMT represents a promising strategy for inhibiting metastatic tumors. Herein, a series of new canadine platinum(IV) conjugates with potent antiproliferative and antimetastatic activities were developed, which activated by suppressing EMT and provoking immune response in tumors besides causing DNA injury. The complexes could covalently conjugate to DNA and induce mitochondria-mediated apoptosis via Bcl-2/Bax/caspase3 signaling. The EMT process was remarkably inhibited by suppressing the Wnt/β-catenin pathway, reversing the inflammatory tumor microenvironment, and inhibiting the HIF-1α pathway, which further resulted in the inhibited angiogenesis in tumors. Moreover, the antitumor immunity was elevated by blocking immune checkpoints PD-L1 and CD47 accompanied by the improvement of CD3+ and CD8+ T lymphocytes and the macrophage polarization from M2- toward M1-type simultaneously in tumors.
研究领域:
癌症生物学
·
药理学
·
免疫学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）