Autonomous metal-organic framework nanorobots for active mitochondria-targeted cancer therapy

Science Advances, Journal Year: 2023, Volume and Issue: 9(23)

Published: June 9, 2023

Nanorobotic manipulation to access subcellular organelles remains unmet due the challenge in achieving intracellular controlled propulsion. Intracellular organelles, such as mitochondria, are an emerging therapeutic target with selective targeting and curative efficacy. We report autonomous nanorobot capable of active mitochondria-targeted drug delivery, prepared by facilely encapsulating mitochondriotropic doxorubicin-triphenylphosphonium (DOX-TPP) inside zeolitic imidazolate framework-67 (ZIF-67) nanoparticles. The catalytic ZIF-67 body can decompose bioavailable hydrogen peroxide overexpressed tumor cells generate effective movement presence TPP cation. This nanorobot-enhanced targeted delivery induces mitochondria-mediated apoptosis mitochondrial dysregulation improve vitro anticancer effect suppression cancer cell metastasis, further verified vivo evaluations subcutaneous model orthotopic breast model. unlocks a fresh field operation organelle access, thereby introducing next generation robotic medical devices organelle-level resolution for precision therapy.

Language: Английский

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Mitochondrial Localized In Situ Self‐Assembly Reprogramming Tumor Immune and Metabolic Microenvironment for Enhanced Cancer Therapy

Advanced Materials, Journal Year: 2024, Volume and Issue: 36(15)

Published: Jan. 8, 2024

Abstract The inherent immune and metabolic tumor microenvironment (TME) of most solid tumors adversely affect the antitumor efficacy various treatments, which is an urgent issue to be solved in clinical cancer therapy. In this study, a mitochondrial localized situ self‐assembly system constructed remodel TME by improving immunogenicity disrupting plasticity cells. peptide‐based drug delivery can pre‐assembled into nanomicelles vitro form functional nanofibers on mitochondria through cascade‐responsive process involving reductive release, targeted enrichment, self‐assembly. organelle‐specific self‐assemblyeffectively switches role mitophagy from pro‐survival pro‐death, finally induces intense endoplasmic reticulum stress atypical type II immunogenic cell death. Disintegration ultrastructure also impedes cells, greatly promotes immunosuppresive remodeling immunostimulatory TME. Ultimately, effectively suppresses metastases, converts cold hot with enhanced sensitivity radiotherapy checkpoint blockade This study offers universal strategy for spatiotemporally controlling supramolecular sub‐organelles determine fate enhance

Language: Английский

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The Common Hallmarks of Aging, Circadian Rhythms and Cancer: Implications for Therapeutic Strategies

Research, Journal Year: 2025, Volume and Issue: 8

Published: Jan. 1, 2025

The intricate relationship between cancer, circadian rhythms, and aging is increasingly recognized as a critical factor in understanding the mechanisms underlying tumorigenesis cancer progression. Aging well-established primary risk for while disruptions rhythms are intricately associated with progression of various tumors. Moreover, itself disrupts leading to physiological changes that may accelerate development. Despite these connections, specific interplay processes their collective impact on remains inadequately explored literature. In this review, we systematically explore influence We discuss how core genes tumor prognosis, highlighting shared hallmarks such genomic instability, cellular senescence, chronic inflammation. Furthermore, examine aging, focusing crosstalk contributes tumorigenesis, proliferation, apoptosis, well metabolism stability. By elucidating common pathways linking review provides new insights into pathophysiology identifies potential therapeutic strategies. propose targeting regulation could pave way novel treatments, including chronotherapy antiaging interventions, which offer important benefits clinical management cancer.

Language: Английский

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Molecular and metabolic regulation of immunosuppression in metastatic pancreatic ductal adenocarcinoma

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: July 24, 2023

Immunosuppression is a hallmark of pancreatic ductal adenocarcinoma (PDAC), contributing to early metastasis and poor patient survival. Compared the localized tumors, current standard-of-care therapies have failed improve survival patients with metastatic PDAC, that necessecitates exploration novel therapeutic approaches. While immunotherapies such as immune checkpoint blockade (ICB) vaccines emerged promising treatment modalities in certain cancers, limited responses been achieved PDAC. Therefore, specific mechanisms regulating response immunotherapy must be explored. The immunosuppressive microenvironment driven by oncogenic mutations, tumor secretome, non-coding RNAs, microbiome persists throughout PDAC progression, allowing neoplastic cells grow locally metastasize distantly. escaping host surveillance are unique molecular, immunological, metabolic characteristics. Following chemokine exosomal guidance, these organ-specific pre-metastatic niches (PMNs) constituted local resident cells, stromal fibroblasts, suppressive metastasis-associated macrophages, neutrophils, myeloid-derived suppressor cells. differs from primary tumors cell composition, functionality, metabolism. Thus far, multiple molecular pathways, distinct identified dampen effector functions, confounding This review describes major immunoregulatory pathways contribute progression limit outcomes Overall, we highlight vulnerabilities attributable factors discuss whether targeting immunological "hot spots" could immunotherapies.

Language: Английский

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Mitochondrial dysfunction at the crossroad of cardiovascular diseases and cancer

Journal of Translational Medicine, Journal Year: 2023, Volume and Issue: 21(1)

Published: Sept. 19, 2023

A large body of evidence indicates the existence a complex pathophysiological relationship between cardiovascular diseases and cancer. Mitochondria are crucial organelles whose optimal activity is determined by quality control systems, which regulate critical cellular events, ranging from intermediary metabolism calcium signaling to mitochondrial dynamics, cell death mitophagy. Emerging data indicate that impaired drives myocardial dysfunction occurring in several heart diseases, including cardiac hypertrophy, infarction, ischaemia/reperfusion damage metabolic cardiomyopathies. On other hand, diverse human cancers also dysregulate promote their initiation progression, suggesting modulating homeostasis may represent promising therapeutic strategy both cardiology oncology. In this review, first we briefly introduce physiological mechanisms underlying system, then summarize current understanding about impact dysregulated functions We discuss key increased risk complications secondary main anticancer strategies, highlighting potential strategies aimed at alleviating impairment-related tumorigenesis. It hoped summary can provide novel insights into precision medicine approaches reduce cancer morbidities mortalities.

Language: Английский

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Impact of platelet-derived mitochondria transfer in the metabolic profiling and progression of metastatic MDA-MB-231 human triple-negative breast cancer cells

Frontiers in Cell and Developmental Biology, Journal Year: 2024, Volume and Issue: 11

Published: Jan. 12, 2024

Introduction: An active role of platelets in the progression triple-negative breast cancer (TNBC) cells has been described. Even platelet-derived extracellular vesicles on migration MDA-MB-231 reported. Interestingly, upon activation, release functional mitochondria into environment. However, impact these metabolic properties remains unclear. Methods: and MDA-MB-231-Rho-0 were co-cultured with platelets, which isolated from donor blood. Mitochondrial transfer was assessed through confocal microscopy flow cytometry, while analyses conducted using a Seahorse XF HS Mini Analyzer. The mito-chondrial DNA (mtDNA) copy number determined via quantitative PCR (qPCR) following platelet co-culture. Finally, cell proliferation colony formation assay performed crystal violet staining. Results Discussion: We have shown that are internalized by co-culture increasing ATP production, oxygen (O 2 ) consumption rate (OCR), proliferation, adaptability. Additionally, we observed depleted mtDNA restore uridine/pyruvate-free culture medium mitochondrial O after indicating reconstitution facilitated mitochondria. In conclusion, our study provides new insights adaptability metastatic TNBC cells.

Language: Английский

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From Crypts to Cancer: A Holistic Perspective on Colorectal Carcinogenesis and Therapeutic Strategies

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(17), P. 9463 - 9463

Published: Aug. 30, 2024

Colorectal cancer (CRC) represents a significant global health burden, with high incidence and mortality rates worldwide. Recent progress in research highlights the distinct clinical molecular characteristics of colon versus rectal cancers, underscoring tumor location's importance treatment approaches. This article provides comprehensive review our current understanding CRC epidemiology, risk factors, pathogenesis, management strategies. We also present intricate cellular architecture colonic crypts their roles intestinal homeostasis. carcinogenesis multistep processes are described, covering conventional adenoma-carcinoma sequence, alternative serrated pathways, influential Vogelstein model, which proposes sequential

Language: Английский

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Extracellular vesicles activated cancer-associated fibroblasts promote lung cancer metastasis through mitophagy and mtDNA transfer

Journal of Experimental & Clinical Cancer Research, Journal Year: 2024, Volume and Issue: 43(1)

Published: June 3, 2024

Abstract Background Studies have shown that oxidative stress and its resistance plays important roles in the process of tumor metastasis, mitochondrial dysfunction caused by DNA (mtDNA) damage is an molecular event stress. In lung cancer, normal fibroblasts (NFs) are activated as cancer-associated (CAFs), act realms microenvironment (TME) with consequences for growth metastasis. However, activation mechanism whether it participates metastasis through antioxidative remain unclear. Methods The role signaling pathways cell derived extracellular vesicles (EVs) activating NFs characteristic induced CAFs (iCAFs) were measured transmission electron microscopy, nanoparticle tracking analysis, immunofluorescence, collagen contraction assay, quantitative PCR, immunoblotting, luciferase reporter assay membrane potential detection. Mitochondrial genome single nucleotide polymorphism sequencing used to investigate transport mtDNA from iCAFs ρ 0 cells, which cells depletion mtDNA. Further, effects on function, analysed co-culture models both vitro vivo, using succinate dehydrogenase, glutathione oxygen consumption rate measurements, CCK-8 transwell xenotransplantation experiments well situ hybridization immunohistochemistry. Results Our findings revealed EVs high-metastatic cancer packaged miR-1290 directly targets MT1G, leading AKT inducing conversion CAFs. exhibit higher levels autophagy mitophagy more release, reactive species (ROS) could further promote this process. After cocultured conditioned medium (CM) iCAFs, may restore function acquisition CAFs, promotes Conclusions These results elucidate a novel tumor-derived can transferring restoring result stress, provide new therapeutic target

Language: Английский

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Mechanisms of breast cancer metastasis

Clinical & Experimental Metastasis, Journal Year: 2021, Volume and Issue: 39(1), P. 117 - 137

Published: May 5, 2021

Abstract Invasive breast cancer tends to metastasize lymph nodes and systemic sites. The management of metastasis has evolved by focusing on controlling the growth disease in breast/chest wall, at metastatic sites, initially surgery alone, then a combination with radiation, later adding treatments form chemotherapy, hormone manipulation, targeted therapy, immunotherapy other aimed inhibiting proliferation cells. It would be valuable for us know how metastasizes; such knowledge likely encourage development therapies that focus mechanisms might even allow avoid toxic are currently used this disease. For example, if we had drug gene is critical metastasis, able cure vast majority patients cancer. By bringing together scientists expertise molecular aspects those mechanical paper probes interesting cascade, further enlightening our efforts improve outcome from treatments.

Language: Английский

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The chromatin remodeler CHD6 promotes colorectal cancer development by regulating TMEM65-mediated mitochondrial dynamics via EGF and Wnt signaling

Cell Discovery, Journal Year: 2022, Volume and Issue: 8(1)

Published: Dec. 6, 2022

Chromodomain helicase DNA binding protein (CHD) family plays critical roles in regulating gene transcription. The is linked to cancer disease, but the member's role tumorigenesis remains largely unknown. Here, we report that CHD6 highly expressed colorectal (CRC). knockdown inhibited cell proliferation, migration, invasion, and tumorigenesis. Consistently, Villin-specific Chd6 knockout mice attenuates formation AOM/DSS model. We found aberrant EGF signals promoted stability of by diminishing ubiquitin-mediated degradation. signal inhibits GSK3β activity, which turn prevents phosphodegron CHD6, thereby hindering E3 ligase FBXW7-mediated ubiquitination CHD6's chromatin remodeler activity engages Wnt signaling transcription factor TCF4 facilitate transcriptional expression TMEM65, a mitochondrial inner membrane involved ATP production dynamics. In addition, also an upstream regulator CHD6. promoter contains β-catenin site, can be transcriptionally activated ligand TMEM65 Thus CHD6-TMEM65 axis regulated both pathways through two different mechanisms. further illustrate deregulated co-administration inhibitor LGK974 anti-EGFR monoclonal antibody cetuximab restricted growth patient-derived xenografts CRC. Targeting may effective for intervention.

Language: Английский

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