CELL
·
2024
·
IF 45.5
Feng Lin,Shenyi Yin,Zijian Zhang,Ying Yu,Haoming Fang,Zhen Liang,Rujie Zhu,Haitao Zhou,Jianjie Li,Kunxia Cao,Weiming Guo,Shan Qin,Yuxuan Zhang,Chenghao Lu,Han Li,Shibo Liu,Heng Zhang,Buqing Ye,Jian Lin,Yan Li,Xiaozheng Kang,Jianzhong Jeff Xi,Peng R. Chen
Although immunotherapy has revolutionized cancer treatment, its efficacy is affected by multiple factors, particularly those derived from the complexity and heterogeneity of the tumor-immune microenvironment (TIME). Strategies that simultaneously and synergistically engage multiple immune cells in TIME remain highly desirable but challenging. Herein, we report a multimodal and programmable platform that enables the integration of multiple therapeutic modules into single agents for tumor-targeted co-engagement of multiple immune cells within TIME. We developed the triple orthogonal linker (T-Linker) technology to integrate various therapeutic small molecules and biomolecules as multimodal targeting chimeras (Multi-TACs). The EGFR-CD3-PDL1 Multi-TAC facilitated T-dendritic cell co-engagement to target solid tumors with excellent efficacy, as demonstrated in vitro , in several humanized mouse models and in patient-derived tumor models. Furthermore, Multi-TACs were constructed to coordinate T cells with other immune cell types. The highly modular and programmable feature of our Multi-TACs may find broad applications in immunotherapy and beyond.
研究领域:
免疫学
·
肿瘤学
·
生物技术
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
DEVELOPMENTAL CELL
·
2023
·
IF 11.8
Xue-Lian Sun,Zhen-Hua Chen,Xize Guo,Jingjing Wang,Mengmeng Ge,Samuel Zheng Hao Wong,Ting Wang,Si Li,Mingze Yao,Laura A. Johnston,Qing-Feng Wu
Cell competition acts as a quality-control mechanism that eliminates cells less fit than their neighbors to optimize organ development. Whether and how competitive interactions occur between neural progenitor cells (NPCs) in the developing brain remains unknown. Here, we show that endogenous cell competition occurs and intrinsically correlates with the Axin2 expression level during normal brain development. Induction of genetic mosaicism predisposes Axin2-deficient NPCs to behave as "losers" in mice and undergo apoptotic elimination, but homogeneous ablation of Axin2 does not promote cell death. Mechanistically, Axin2 suppresses the p53 signaling pathway at the post-transcriptional level to maintain cell fitness, and Axin2-deficient cell elimination requires p53-dependent signaling. Furthermore, mosaic Trp53 deletion confers a "winner" status to p53-deficient cells that outcompete their neighbors. Conditional loss of both Axin2 and Trp53 increases cortical area and thickness, suggesting that the Axin2-p53 axis may coordinate to survey cell fitness, regulate natural cell competition, and optimize brain size during neurodevelopment.
研究领域:
神经科学
·
发育生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cancer Nanotechnology
·
2024
·Vol. 15
·期 1
·1-16
·
IF 4.5
Jiang Qiping,Yao Fengjiao,An Yacong,Lai Xialian,Li Xundou,Yu Zhen,Yang Xian-Da
Background PD-1/PD-L1 blockade plays a crucial role in cancer immunotherapy. Exploration of new technologies to further enhance the efficacy of PD-1/PD-L1 blockade is therefore of potential medical importance. Nanotherapeutics can accumulate in tumor tissues due to enhanced permeability and retention (EPR) effects. In this study, a novel nanotherapeutic for cancer immunotherapy was implemented with albumin nanoparticles functionalized by both PD-1 and PD-L1 aptamers.Results Albumin nanoparticles (NP) were functionalized with either PD-1 aptamers (PD1-NP), PD-L1 aptamers (PDL1-NP), or both types of aptamers (PD1-NP-PDL1). Average sizes of PD1-NP, PDL1-NP, and PD1-NP-PDL1 were 141.8 nm, 141.8 nm, and 164.2 nm, respectively. PD1-NP had good affinity for activated T cells that expresses PD-1. Similarly, PDL1-NP could bind with MDA-MB-231 or CT26 tumor cells that express PD-L1. Moreover, the bispecific PD1-NP-PDL1 could bind with both the activated T cells and the PD-L1-expressing tumor cells, and tether the two type of cells together. Functionally, aptamer-modified nanoparticles exhibited stronger immune-stimulating effects vs. free aptamers. Specifically, PD1-NP or PDL1-NP induced stronger lymphocyte-mediated cytotoxicity against PD-L1-expressing tumor cells in vitro vs. free PD-1 or PD-L1 aptamers. Animal studies also showed that PD1-NP or PDL1-NP significantly improved antitumor efficacy against CT26 colon cancer in vivo vs. free PD-1 or PD-L1 aptamers. Importantly, the bispecific PD1-NP-PDL1 further boosted the in vivo antitumor efficacy compared with PD1-NP or PDL1-NP, without raising systemic toxicity.Conclusion The results suggest that the bispecific PD1-NP-PDL1 is a promising nanotherapeutic to improve the efficacy of PD-1/PD-L1 blockade, and may have application potential in colon cancer treatment.
研究领域:
肿瘤学
·
纳米医学
·
免疫学
✓ 已验证
DOI
高影响因子
BIOMATERIALS
·
2025
·
IF 12.9
Shiman Lu,Zhaoqing Shi,Chendi Ding,Wenyan Wang,Weilang Zhang,Li Huang,Jiachan Lin,Xinpei Wang,Ran Luo,Xiaowei Zeng,Wenhu Zhou,Hongzhong Chen,Qiangsong Wang,Lin Mei
The targeted protein degradation (TPD) strategy modulates tumor growth pathways by degrading proteins of interest (POIs) and has reshaped anti-tumor drug research and development. Recently, the emergence of photodegradation-targeting chimeras (PDTACs) and laser irradiation at specific sites enables precise spatiotemporal controllability of TPD. Capitalizing on the advances of PDTACs, herein, we report a nanoplatform for efficiently delivering PDTAC molecule for photodegradation of bromodomain-containing protein 4 (BRD4) proteins, the key activators of oncogenic transcription. The PDTAC molecule, named as PPa-JQ1, is synthesized through the covalent attachment of the BRD4-targeting ligand JQ1-acid, to the photosensitizer pyropheophorbide-a (PPa), utilizing a 1,6-hexanediamine linker. The PPa-JQ1 is further encapsulated by human serum albumin (HSA) to obtain the HSA@PPa-JQ1 nanoplatform, which facilitates targeted and efficacious delivery to melanoma lesions. Both in vitro and in vivo therapeutic outcomes demonstrate that HSA@PPa-JQ1 can efficiently generate reactive oxygen species (ROS) to degrade BRD4 upon light irradiation, which eventually induces tumor death. Our study represents the first case to validate the anti-tumor therapeutic efficacy of PDTACs by systemic administration, providing the foundation for further application of PDTACs.
研究领域:
肿瘤学
·
药学
·
纳米技术
·
光化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2023
·
IF 7.3
Mingming Qi,Hui Zhong,Zhaoyan Cheng,Shujie Chen,Han Xiao,Jing Shang,Li Chen,Jianbo Sun
Activating Nrf2 through inhibiting Keap1 has been proven to alleviate oxidative stress and related diseases, including nonalcoholic fatty liver disease (NAFLD). Traditional Keap1 inhibitors could not avoid the “off-target” effects, but using proteolysis targeting chimera (PROTAC) technology to induce Keap1 degradation might be an effective strategy to find potential NAFLD improving agents. Thus, several PROTACs were designed and synthesized by harnessing CDDO as the Keap1 ligand in this study. PROTAC I-d exhibited optimal Keap1 degradation activity, which could increase the Nrf2 level and alleviate oxidative stress in free fatty acid-induced AML12 cells and the liver of mice fed with a methionine-choline-deficient diet. Moreover, compared with CDDO, PROTAC I-d displayed significant advantages in inhibiting hepatic steatosis, steatohepatitis, and fibrosis in the in vivo and in vitro models of NAFLD. In addition, PROTAC I-d also showed lower in vivo toxicity than CDDO. All these results suggested that PROTAC I-d might be a potential improving agent for NAFLD.
研究领域:
药理学
·
肝病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2023
·
IF 7.3
Yichen Tong,Wentao Zhu,Jian Chen,Wenqian Zhang,Fang Xu,Jiyan Pang
Targeted protein degradation (TPD) confers knockdown of “undruggable” targets such as alpha-synuclein (αSyn), a pathogenic protein in multiple neurodegenerative diseases. Though many of these proteins were mainly degraded through the autophagy-lysosome pathway (ALP), few TPD tools harnessing the ALP were reported. Herein, we developed a strategy termed autophagosome-anchoring chimera (ATACC), in which the protein of interest (POI) can be anchored to microtubule-associated protein-1 light chain-3B (LC3B) on the autophagosome with the assistance of an LC3-interacting region (LIR)-containing bifunctional peptide, and the selective autophagy of the POI is thus facilitated. A series of αSyn-targeting ATACC peptides were designed and synthesized. Biological evaluations demonstrated that these compounds could degrade αSyn specifically and effectively through a “chemical-induced cargo recognition–ALP degradation” mechanism. The neuroprotective effects of ATACC peptide P1 were further validated in vitro and in vivo. Collectively, our results provided a new TPD tool and revealed a potential therapeutic strategy against synucleinopathies.
研究领域:
神经科学
·
药理学
·
分子生物学
·
治疗学
✓ 已验证
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Xinglin Tao,Peng Yang,Zhaoqi Liu,Siyao Qin,Jun Hu,Zhao-Xia Huang,Xiangyu Chen,Jin-Ping Qu
The energy conversion efficiency of a triboelectric nanogenerator (TENG) is severely limited by the charge density of triboelectric materials, while drastic and unavoidable charge decay happens during contact due to the insufficient charge retention capacity of positive triboelectric materials. Here, elaborately synthesized acid-ion-doped pyridine-based polybenzimidazole processing with strong charge retention capability is demonstrated to couple with negatively corona-polarized electrets. As illustrated by thermal stimulation and an ion mass spectrometer, the formation of acid-ion chimerism processes high activation energy for stored charges, and the selective anion migration can compensate the escape of polarized charge. Accordingly, the charge density can reach up to 596 μC m–2 and the charge retention rate reaches 49.7%, which is so far the highest intrinsic charge density obtained in the open air. Thus, the ionic chimerism strategy provides an effective way to suppress the charge escaping in the open air and gives a great expandable avenue for the material challenges of TENG’s practical deployment.
研究领域:
材料科学
·
纳米技术
·
能量转换
·
静电学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Science Advances
·
2024
·Vol. 10
·期 25
·
IF 11.7
Yazhen Wang,Lianyi Yang,Chenxing Yan,Yufan Du,Tinghua Li,Wenqing Yang,Lei Lei,Bin He,Huile Gao,Nicholas A. Peppas,Jun Cao
Autophagy-targeting chimera (AUTAC) has emerged as a powerful modality that can selectively degrade tumor-related pathogenic proteins, but its low bioavailability and nonspecific distribution significantly restrict their therapeutic efficacy. Inspired by the guanine structure of AUTAC molecules, we here report supramolecular artificial Nano-AUTACs (GM NPs) engineered by AUTAC molecule GN [an indoleamine 2,3-dioxygenase (IDO) degrader] and nucleoside analog methotrexate (MTX) through supramolecular interactions for tumor-specific protein degradation. Their nanostructures allow for precise localization and delivery into cancer cells, where the intracellular acidic environment can disrupt the supramolecular interactions to release MTX for eradicating tumor cells, modulating tumor-associated macrophages, activating dendritic cells, and inducing autophagy. Specifically, the induced autophagy facilitates the released GN for degrading immunosuppressive IDO to further enhance effector T cell activity and inhibit tumor growth and metastasis. This study offers a unique strategy for building a nanoplatform to advance the field of AUTAC in tumor immunotherapy.
研究领域:
癌症治疗
·
纳米技术
·
免疫治疗
·
蛋白质降解
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）