Advanced Healthcare Materials
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2024
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IF 10
Hairui Zhang,Xiaoling Xu,Xin Shou,Wucan Liao,Chengkang Jin,Changjiang Chen,Chen Zhang,Wenhua Gao,Junfeng Zhang,Weihong Ge,Liyun Shi
Cellular senescence is a significant risk factor for aging and age-related diseases (ARD). The canonical senolytics Dasatinib and Quercetin (DQ) have shown promise in clearing senescent cells (SnCs); however, the lack of selectivity poses a challenge in achieving optimal outcomes. Despite the recent occurrence of the nanomaterial-based approaches targeting SnCs, limited therapeutic effects and potential toxicity still remain a major concern. Herein, we developed a “double locks-like” nanoplatform that integrated Galactan coating and mesoporous polydopamine to encase the senolytic drug DQ. By this way, DQ was only released in SnCs that were featured with higher levels of β-galactosidase (β-gal) and low PH. Additionally, the nanoparticles were equipped with 2,2,6,6-Tetramethylpiperidine-1-oxyl (Tempo) to gain enhanced photothermal converting potential. Consequently, the synthesized nanosenolytics demonstrated remarkable specificity and efficacy in eradicating SnCs, and accordingly reversed pulmonary fibrosis in mice without affecting normal tissues. Upon exposure of near-infrared (NIR) light, the nanoparticles demonstrated to efficiently remove senescent tumor cells inducted by chemotherapy, thereby hindering the outgrowth and metastasis or breast cancer. Collectively, the present study develops an “On/Off” switchable nanoplatform in response to SnCs, and produces a more safe, efficient and feasible way to delay aging or alleviate age-associated diseases. This article is protected by copyright. All rights reserved
研究领域:
衰老
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纳米技术
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药理学
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癌症研究
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治疗学
✓ 已验证
DOI
PubMed
高影响因子
Fundamental Research
·
2024
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IF 5.7
Rong Li,Yaohua Wei,Changhao Xiong,Jingwei Wang,Yixuan Lin,Ronghui Deng,Hao Qin,Yang Chen,Nan Li,Guyu Zheng,Yuanyuan Lv,Jian Shi,Tingting Yu,Yiye Li,Jing Wang,Ruifang Zhao,Changsheng Liu,Guangjun Nie
The senescence of bone marrow-derived mesenchymal stem cells is involved in osteoporosis. The combination of dasatinib and quercetin has been explored to alleviate bone loss by efficiently reducing senescent cell populations. However, senolytic therapy by dasatinib and quercetin requires a precise ratio for better therapeutic effects, which is hard to achieve by oral administration. Meanwhile, the poor water solubility of these compounds limits their bioavailability, and their non-specific action could hamper effective penetration and targeting within relevant tissues. Herein, we developed alendronate-functionalized liposomes carrying dasatinib and quercetin (Aln-Lipo-DQ), focusing mainly on senescence-associated osteoporosis induced by chemotherapy or radiotherapy. Alendronate helps liposomes deliver dasatinib and quercetin to the femur and tibias, effectively removing senescent cells from bone tissue and increasing bone volume fraction from 5.05% to 11.95% in the chemotherapy-induced osteoporosis mouse model. We also found a 2.91-fold increase in bone volume fraction in Aln-Lipo-DQ treated groups compared to the control in radiotherapy models. This selectively targeting bone and reducing senescent cells holds great promise for cancer treatment-related and senescence-associated bone disorders.
研究领域:
医学
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药理学
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生物技术
✓ 已验证
DOI
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2026
·Vol. 24
·期 1
·269
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IF 15
Fan Yonggang,Wang Ze-Han,Zhang Xu,Dong Yu,Liu Xin,Luo Gan,Yang Houzhi,Li Huinan,Wang Zicheng,Tang Qiong,Jin Xin,Guo Dong-Sheng,Sun Tianwei
Current clinical management of fractures relies largely on surgical intervention and systemic pharmacotherapy, both of which are frequently associated with side effects and largely neglect early microenvironmental abnormalities. Precise elimination of senescent cells at the early stage may offer a more efficient means of restoring microenvironmental homeostasis and resetting regenerative dynamics. To this end, we designed and synthesized a multifunctional supramolecular nanoplatform, Asp 10 SAC4A, based on combination of host–guest recognition and self-assembly to simultaneously address three fundamental challenges in selectively eliminating senescent cells at the fracture site: inadequate targeting, insufficient responsiveness, and poor coordination of multi-drug delivery. The platform consists of an azocalix [ 4 ]arene modified with a deca-aspartate (Asp 10 ) peptide for selective binding to newly exposed hydroxyapatite at fracture sites, enabling active localization. Simultaneously, Dasatinib and Quercetin are co-loaded in a controlled ratio, and triggered for rapid release through the hypoxia-responsive mechanism of the azo groups, achieving microenvironment-specific “source-clearing” therapy. This strategy significantly alleviates inflammation, enhances osteogenesis and accelerates fracture healing. These results highlight the crucial role of selectively targeting senescent cells in the early phase of fracture and offer an innovative therapeutic approach that improves treatment efficiency and prognosis. Overall, this study aims to establish a fracture-site–activated senolytic delivery strategy that integrates fracture targeting, hypoxia-triggered release, and combination therapy, thereby enabling precise early-stage anti-senescence intervention to accelerate fracture healing. Graphic abstract
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2024
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IF 6.7
Wentao Sun,Yue Gao,Yubing Wu,Wei Wu,Chaofan Wang,JiaXiao Chen,Changjiao Luan,Ming Hua,Weili Liu,Weijuan Gong,Xingjie Ma
Background Accumulation of senescent cells in tissues and their downstream effect programs have emerged as key drivers of aging and age-associated pathologies. Recent progresses in senotherapeutics indicated that either selectively killing senescent cells with senolytics or suppressing the senescence-associated secretory phenotype (SASP) secretion using senomorphics contributes to extending of the healthy lifespan and alleviating numerous age-related disorders in mice. Purpose However, the potential side-effects and long-term cytotoxicity of the above novel compounds have not yet been determined. Therefore, it seems to be more efficient to explore new senotherapeutical functions from approved drugs. Methods The effects of valproic acid (VPA), a derivative of valine, in cellular senescence were evaluated by senescence-associated β galactosidase (SA-β-Gal) staining, flow cytometry and western blot (WB). The cell viability was tested using CCK-8 kits. Cell apoptosis was detected by Annexin V-EGFP/PI apoptosis detection kit. Cell autophagy was checked using GFP-RFP-LC3 ratiometric plasmid. The roles of VPA in lung aging were investigated by in vivo experiments using H&E and Masson staining, WB, as well as electronic microscope strategies. Results Here we identified VPA was able to induce an over-accumulation of reactive oxygen species (ROS) (>1.5 times increasing) and apoptosis (>2 times increasing) of senescent cells. Mechanistically, VPA activated the phospholipid modifying enzyme membrane-bound O-acyltransferase domain-containing protein 1 (MBOAT1), which was repressed during senescence, then promoted mitochondrial autophagy and apoptosis. In addition, VPA was also found to alleviate therapy induced abnormal mitochondria and lung aging phenotype (>1.5 times decreasing of lung fibrosis markers and >2.5 times increasing of naïve/memory CD4+ or CD8+ cells) in vivo . Conclusion Taken together, our study demonstrated that VPA was able to selectively killing senescent cells both in vitro and in vivo , and thus shedding light on new functions and novel potential application of VPA in anti-aging and anti-age-associated diseases.
研究领域:
衰老
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药理学
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细胞生物学
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治疗学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）