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- Global to local burdens, inequalities, and achievable frontiers of child and adolescent malignant neoplasm of bone and articular cartilage across 953 countries and sublocations, 1980–2040, with deep learning-based forecastsPublication . Cai, Wenxiang; Wu, Yaling; Xue, Mingyang; Chu, Yihang; Rawaf, Salman; Bui, Marilyn M.; Broto, Javier Martín; Zhang, Heping; Szarpak, Lukasz; Pan, Liming; Huang, Baozhen; Xiong, Yiming; Li, Fei; Zeng, You; Chen, Kai; Zhong, Claire Chenwen; Peng, Hao; Ye, Pengpeng; Conde, João; Peng, Fei; Lin, Queran; Jin, Wenyi; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); Centre for Toxicogenomics and Human Health (ToxOmics); Elsevier (Singapore) Pte LtdBackground Malignant neoplasm of bone and articular cartilage (MNBAC), a major cause of cancer-related mortality, disproportionately impacts children and adolescents. However, comprehensive and future-oriented studies are still lacking. Methods We systematically analyzed global-to-subnational MNBAC burdens, inequalities, and ideal achievable frontiers among those under 20 years old across 953 locations from 1980 to 2021. An advanced attention-based deep-learning pipeline was created for precise forecasting. Results From 1990 to 2021, the global prevalence and incidence rate of MNBAC among those aged <20 years increased by 14.7 % and 14.3 %, respectively, leading to 139,154 prevalent cases by 2021. This disproportionately affected males and increased progressively with age, peaking in adolescents aged 15–19 years. Despite a slight global decline in MNBAC mortality, notable increases were observed in low-middle SDI region. 87.3 % of countries and 93.8 % of subnational locations experiencing increased mortality were situated in low to middle SDI regions, exemplified by Tokelau (377.8 %) and Indonesia's West Papua (148.6 %). Concurrently, the global YLD/YLL ratio for those <20 years increased, reflecting the ongoing transition from fatal to non-fatal burdens. This shift mainly impacted socio-economically advantaged settings, as 61 % of the top 100 countries were categorized as high and high-middle SDI. However, substantial gaps remain globally, with at least 94.1 % of countries and 81.4 % of subnational locations failing to meet achievable frontiers by 2021. Forecasts to 2040 anticipate further increases in incidence and stagnation in mortality, alongside widening disparities. Approximately 60.0 % of 672 subnational locations are forecasted to exhibit rising prevalence, with 41.2 % in the UK. By 2040, 30.0 % of the top 100 high-prevalence subnational locations will likely be in Sub-Saharan Africa, including 56 % in the UK. Mortality rates are forecasted to remain highest in low SDI region, especially in Eastern Sub-Saharan Africa, accounting for 47.7 % in Kenya alone. Conclusion The MNBAC burden remains high, especially among adolescents, with anticipated increases in lower-income areas, necessitating targeted healthcare policies and increased investment. The Translational Potential of this Article This study highlights the growing global burden of MNBAC and the urgent need for age-specific prevention, early detection, and equitable access to healthcare. Enhancing cancer registries, expanding financial protection, and integrating MNBAC management into national cancer control strategies could help reduce disparities and improve outcomes for affected children and adolescents.
- A genetic variant in the 3′-UTR of PIWIL4 confers risk for extreme phenotypes of male infertility by altering miR-215 and miR-136 binding affinityPublication . González-Muñoz, Sara; Cerván-Martín, Miriam; Cerván Martín, Miriam; Guzmán-Jiménez, Andrea; Rodríguez-Martín, Ana Isabel; Garrido, Nicolás; Castilla, José A.; Gonzalvo, M. Carmen; Clavero, Ana; Molina, Marta; Molina Romero, Marta; Vilches, Miguel Ángel; Espuch-Oliver, Andrea; Maldonado, Vicente; García-Peña, María Luisa; Galiano-Gutiérrez, Noelia; Santamaría, Esther; González, Cristina; Quintana-Ferraz, Fernando; Quintana Ferraz, Fernando; Gómez, Susana; Amorós, David; Martínez-Granados, Luis; Ortega-González, Yanira; Ortega González, Yanira; Burgos, Miguel; Pereira-Caetano, Iris; Pinto, Graça S.; Aguiar, Ana; Pereira, Isabel S.; López-Rodrigo, Olga; Bassas, Lluís; Seixas, Susana; Seixas, Susana; Gonçalves, João; Gonçalves, João; Lopes, Alexandra M.; Larriba, Sara; LARRIBA, SARA; Bossini-Castillo, Lara; Bossini-Castillo, Lara; Carmona, F. David; Palomino-Morales, Rogelio J.; Centre for Toxicogenomics and Human Health (ToxOmics); NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); Oxford University PressSTUDY QUESTION What is the functional impact of the rs508485 genetic polymorphism, located in the 3′-untranslated region (UTR) region of the PIWIL4 gene, on non-obstructive azoospermia (NOA)? SUMMARY ANSWER The rs508485 genetic variant contributes to the pathogenesis of extreme patterns of NOA by modulating PIWIL4 expression through microRNA (miRNA) interactions. WHAT IS KNOWN ALREADY Male infertility represents a significant global health challenge with profound societal and economic consequences. One of the most severe forms of male infertility is NOA, which is characterized by severe spermatogenic failure (SPGF) of idiopathic origin in most cases. Cumulating knowledge increasingly suggests that this idiopathic form of NOA may represent a multifactorial condition involving complex interactions between genetic and environmental factors. The PIWI protein subfamily, particularly PIWIL4, plays a pivotal role in spermatogenesis by processing PIWI-interacting RNAs, which silence retrotransposons to protect genomic integrity. Genetic variations in this gene have been found to be associated with susceptibility to NOA. STUDY DESIGN, SIZE, DURATION A case-control study was conducted in a European cohort including 1516 infertile men with SPGF and 2451 fertile controls. Logistic regression and functional assays were employed to investigate the functional role of the rs508485 polymorphism in PIWIL4. PARTICIPANTS/MATERIALS, SETTING, METHODS Participants were genotyped for the rs508485 polymorphism. Associations between the polymorphism and NOA phenotypes, including Sertoli cell-only (SCO) syndrome and testicular sperm extraction (TESE) outcomes, were assessed. In silico tools predicted miRNA binding effects, which were subsequently validated using luciferase reporter assays. MAIN RESULTS AND THE ROLE OF CHANCE The T allele of rs508485 was significantly associated with the SCO phenotype (P = 2.69E-03, OR = 1.34) and unfavourable TESE outcomes (P = 1.09E-03, OR = 1.54). In silico analyses predicted that the rs508485 variant might alter binding sites in the 3′-UTR region of PIWIL4 for different miRNAs, such as hsa-miR-215-3p and hsa-miR-136-3p. Functional validation using luciferase assays confirmed that these miRNAs differentially bind to the T and C alleles of this polymorphism, influencing PIWIL4 regulation. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION The study is limited to a single genetic polymorphism and functional assays were performed in vitro. Additional studies are required to validate these findings across diverse populations and explore additional genetic interactions. WIDER IMPLICATIONS OF THE FINDINGS These findings highlight the critical role of miRNA regulation in extreme forms of male infertility by influencing the expression of essential spermatogenesis genes, such as PIWIL4. Our study sheds light on the genetic mechanisms underlying spermatogenesis and suggests potential therapeutic targets for NOA. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the Spanish Ministry of Economy and Competitiveness through the Spanish National Plan for Scientific and Technical Research and Innovation (grant: PID2020-120157RB-I00 funded by MICIU/AEI/10.13039/501100011033; and grant: PID2023-152215OB-I00 funded by MICIU/AEI/10.13039/501100011033 and ERDF, EU). M.C.-M is beneficiary of a Juan de la Cierva 2022 postdoctoral fellowship (reference number JDC2022-048561-I) funded by MCIN/AEI/10.13039/501100011033 and European Union NextGenerationEU/PRTR. S.L. received support from "Generalitat de Catalunya"(grant 2021SGR052). S.L. is sponsored by the "Researchers Consolidation Program"from the SNS-Dpt. Salut Generalitat de Catalunya (Exp. CES09/020). S.G.-M. was funded by grant ref. FPU23/02674. S.S. was supported by funds from the Portuguese Foundation for Science and Technology (FCT; 10.54499/DL57/2016/CP1363/CT0019). The authors declare no competing interests.
- Guidance on minimum information requirements (MIR) from designing to reporting human biomonitoring (HBM)Publication . Zare Jeddi, Maryam; Galea, Karen S.; Ashley-Martin, Jillian; Nassif, Julianne; Pollock, Tyler; Poddalgoda, Devika; Kasiotis, Konstantinos M.; Machera, Kyriaki; Koch, Holger M.; López, Marta Esteban; Chung, Ming Kei; Kil, Jihyon; Jones, Kate; Covaci, Adrian; Ait Bamai, Yu; Fernandez, Mariana F.; Kase, Robert Pasanen; Louro, Henriqueta; Silva, Maria J.; Santonen, Tiina; Katsonouri, Andromachi; Castaño, Argelia; Quirós-Alcalá, Lesliam; Lin, Elizabeth Ziying; Pollitt, Krystal; Virgolino, Ana; Scheepers, Paul T.J.; Melnyk, Lisa Jo; Mustieles, Vicente; Cañas Portilla, Ana Isabel; Viegas, Susana; von Goetz, Natalie; Sepai, Ovnair; Bird, Emily; Göen, Thomas; Fustinoni, Silvia; Ghosh, Manosij; Dirven, Hubert; Kwon, Jung Hwan; Carignan, Courtney; Mizuno, Yuki; Ito, Yuki; Xia, Yankai; Nakayama, Shoji F.; Makris, Konstantinos C.; Parsons, Patrick J.; Gonzales, Melissa; Bader, Michael; Dusinska, Maria; Menouni, Aziza; Duca, Radu Corneliu; Chbihi, Kaoutar; Jaafari, Samir El; Godderis, Lode; van Nieuwenhuyse, An; Qureshi, Asif; Ali, Imran; Trindade, Carla Costa; Teixeira, Joao Paulo; Bartonova, Alena; Tranfo, Giovanna; Audouze, Karine; Verpaele, Steven; LaKind, Judy; Mol, Hans; Bessems, Jos; Magagna, Barbara; Waras, Maisarah Nasution; Connolly, Alison; Nascarella, Marc; Yang, Wonho; Huang, Po Chin; Lee, Jueun; Heussen, Henri; Goksel, Ozlem; Yunesian, Masud; Yeung, Leo W.Y.; Souza, Gustavo; Vekic, Ana Maria; Haynes, Erin N.; Hopf, Nancy B.; Centre for Toxicogenomics and Human Health (ToxOmics); NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); Laboratório Associado de Translacção e Inovação para a Saúde Global - LA Real (Pólo ENSP); Comprehensive Health Research Centre (CHRC) - Pólo ENSP; Escola Nacional de Saúde Pública (ENSP); Centro de Investigação em Saúde Pública (CISP/PHRC); ElsevierHuman biomonitoring (HBM) provides an integrated chemical exposures assessment considering all routes and sources of exposure. The accurate interpretation and comparability of biomarkers of exposure and effect depend on harmonized, quality-assured sampling, processing, and analysis. Currently, the lack of broadly accepted guidance on minimum information required for collecting and reporting HBM data, hinders comparability between studies. Furthermore, it prevents HBM from reaching its full potential as a reliable approach for assessing and managing the risks of human exposure to chemicals. The European Chapter of the International Society of Exposure Science HBM Working Group (ISES Europe HBM working group) has established a global human biomonitoring community network (HBM Global Network) to develop a guidance to define the minimum information to be collected and reported in HBM, called the “Minimum Information Requirements for Human Biomonitoring (MIR-HBM)”. This work builds on previous efforts to harmonize HBM worldwide. The MIR-HBM guidance covers all phases of HBM from the design phase to the effective communication of results. By carefully defining MIR for all phases, researchers and health professionals can make their HBM studies and programs are robust, reproducible, and meaningful. Acceptance and implementation of MIR-HBM Guidelines in both the general population and occupational fields would improve the interpretability and regulatory utility of HBM data. While implementation challenges remain—such as varying local capacities, and ethical and legal differences at the national levels, this initiative represents an important step toward harmonizing HBM practice and supports an ongoing dialogue among policymakers, legal experts, and scientists to effectively address these challenges. Leveraging the data and insights from HBM, policymakers can develop more effective strategies to protect public health and ensure safer working environments.
- Trans-ethnic GWAS meta-analysis of idiopathic spermatogenic failure highlights the immune-mediated nature of Sertoli cell-only syndromePublication . González-Muñoz, Sara; González-Muñoz, Sara; Long, Yichen; Guzmán-Jiménez, Andrea; Guzmán-Jiménez, Andrea; Cerván-Martín, Miriam; Higueras-Serrano, Inmaculada; Castilla, José A.; CASTILLA, JOSE ANTONIO; Clavero, Ana; Garrido, Nicolás; Garrido, Nicolas; Luján, Saturnino; Luján, Saturnino; Yang, Xiaoyu; Guo, Xuejiang; Guo, Xuejiang; Liu, Jiayin; Bassas, Lluís; Seixas, Susana; Gonçalves, João; Lopes, Alexandra M.; Larriba, Sara; Bossini-Castillo, Lara; Bossini-Castillo, Lara; Palomino-Morales, Rogelio J.; Wang, Cheng; Wang, Cheng; Hu, Zhibin; HU, Zhibin; Carmona, F. David; Carmona, F. David; Centre for Toxicogenomics and Human Health (ToxOmics); NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); Nature PortfolioNon-obstructive azoospermia, a severe form of male infertility caused by spermatogenic failure (SPGF), has a largely unknown genetic basis across ancestries. To our knowledge, this is the first trans-ethnic meta-analysis of genome-wide association studies on SPGF, involving 2255 men with idiopathic SPGF and 3608 controls from European and Asian populations. Using logistic regression and inverse variance methods, we identify two significant genetic associations with Sertoli cell-only (SCO) syndrome, the most extreme SPGF phenotype. The G allele of rs34915133, in the major histocompatibility complex class II region, significantly increases SCO risk (P = 5.25E-10, OR = 1.57), supporting a potential immune-related cause. Additionally, the rs10842262 variant in the SOX5 gene region is also a genetic marker of SCO (P = 5.29E-09, OR = 0.72), highlighting the key role of this gene in the male reproductive function. Our findings reveal shared genetic factors in male infertility across ancestries and provide insights into the molecular mechanisms underlying SCO.
- Hazard characterization of the mycotoxins enniatins and beauvericin to identify data gaps and improve risk assessment for human healthPublication . Behr, Anne Cathrin; Fæste, Christiane Kruse; Azqueta, Amaya; Tavares, Ana M.; Spyropoulou, Anastasia; Solhaug, Anita; Olsen, Ann Karin; Vettorazzi, Ariane; Mertens, Birgit; Zegura, Bojana; Streel, Camille; Ndiaye, Dieynaba; Spilioti, Eliana; Dubreil, Estelle; Buratti, Franca Maria; Crudo, Francesco; Eriksen, Gunnar Sundstøl; Snapkow, Igor; Teixeira, João Paulo; Rasinger, Josef D.; Sanders, Julie; Machera, Kyriaki; Ivanova, Lada; Gaté, Laurent; Le Hegarat, Ludovic; Novak, Matjaz; Smith, Nicola M.; Tait, Sabrina; Fraga, Sónia; Hager, Sonja; Marko, Doris; Braeuning, Albert; Louro, Henriqueta; Silva, Maria João; Dirven, Hubert; Dietrich, Jessica; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); Centre for Toxicogenomics and Human Health (ToxOmics); Springer VerlagEnniatins (ENNs) and beauvericin (BEA) are cyclic hexadepsipeptide fungal metabolites which have demonstrated antibiotic, antimycotic, and insecticidal activities. The substantial toxic potentials of these mycotoxins are associated with their ionophoric molecular properties and relatively high lipophilicities. ENNs occur extensively in grain and grain-derived products and are considered a food safety issue by the European Food Safety Authority (EFSA). The tolerable daily intake and maximum levels for ENNs in humans and animals remain unestablished due to key toxicological and toxicokinetic data gaps, preventing full risk assessment. Aiming to find critical data gaps impeding hazard characterization and risk evaluation, this review presents a comprehensive summary of the existing information from in vitro and in vivo studies on toxicokinetic characteristics and cytotoxic, genotoxic, immunotoxic, endocrine, reproductive and developmental effects of the most prevalent ENN analogues (ENN A, A1, B, B1) and BEA. The missing information identified showed that additional studies on ENNs and BEA have to be performed before sufficient data for an in-depth hazard characterisation of these mycotoxins become available.
- Age-sex-specific burden of urological cancers attributable to risk factors in China and its provinces, 1990–2021, and forecasts with scenarios simulationPublication . Xue, Mingyang; Guo, Weiheng; Zhou, Yundong; Meng, Jialin; Xi, Yong; Pan, Liming; Ye, Yanfang; Zeng, You; Che, Zhifei; Zhang, Liang; Ye, Pengpeng; Conde, João; Conde, João; Lin, Queran; Jin, Wenyi; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); Centre for Toxicogenomics and Human Health (ToxOmics); ElsevierBackground: As global aging intensifies, urological cancers pose increasing health and economic burdens. In China, home to one-fifth of the world's population, monitoring the distribution and determinants of these cancers and simulating the effects of health interventions are crucial for global and national health. Methods: With Global Burden of Disease (GBD) China database, the present study analyzed age-sex-specific patterns of incidence, prevalence, mortality, disability-adjusted life years (DALYs), years lived with disability (YLDs), and years of life lost (YLLs) in China and its 34 provinces as well as the association between gross domestic product per capita (GDPPC) and these patterns. Importantly, a multi-attentive deep learning pipeline (iTransformer) was pioneered to model the spatiotemporal patterns of urological cancers, risk factors, GDPPC, and population, to provide age-sex-location-specific long-term forecasts of urological cancer burdens, and to investigate the impacts of risk-factor-directed interventions on their future burdens. Findings: From 1990 to 2021, the incidence and prevalence of urological cancers in China has increased, leading to 266,887 new cases (95% confidence interval: 205,304–346,033) and 159,506,067 (12,236,0000–207,447,070) cases in 2021, driven primarily by males aged 55+ years. In 2021, Taiwan, Beijing, and Zhejiang had the highest age-standardized incidence rate (ASIR) and age-standardized prevalence rates of urological cancer in China, highlighting significant regional disparities in the disease burden. Conversely, the national age-standardized mortality rate (ASMR) has declined from 6.5 (5.1–7.8) per 100,000 population in 1990 to 5.6 (4.4–7.2) in 2021, notably in Jilin [−166.7% (−237 to −64.6)], Tibet [−135.4% (−229.1 to 4.4)], and Heilongjiang [−118.5% (−206.5 to −4.6)]. Specifically, the national ASMR for bladder and testicular cancers reduced by −32.1% (−47.9 to 1.9) and −31.1% (−50.2 to 7.2), respectively, whereas prostate and kidney cancers rose by 7.9% (−18.4 to 43.6) and 9.2% (−12.2 to 36.5). Age-standardized DALYs, YLDs, and YLLs for urological cancers were consistent with ASMR. Males suffered higher burdens of urological cancers than females in all populations, except those aged <5 years. Regionally and provincially, high GDPPC provinces have the highest burden of prostate cancer, while the main burden in other provinces is bladder cancer. The main risk factors for urological cancers in 2021 are smoking [accounting for 55.1% (42.7–67.4)], high body mass index [13.9% (5.3–22.4)], and high fasting glycemic index [5.9% (−0.8 to 13.4)] for both males and females, with smoking remarkably affecting males and high body mass index affecting females. Between 2022 and 2040, the ASIR of urological cancers increased from 10.09 (9.19–10.99) to 14.42 (14.30–14.54), despite their ASMR decreasing. Notably, prostate cancer surpassed bladder cancer as the primary subcategory, with those aged 55+ years showing the highest increase in ASIR, highlighting the aging-related transformation of the urological cancer burden. Following the implementation of targeted interventions, smoking control achieved the greatest reduction in urological cancer burden, mainly affecting male bladder cancer (−45.8% decline). In females, controlling smoking and high fasting plasma glucose reduced by 5.3% and 5.8% ASMR in urological cancers. Finally, the averaged mean-square-Percentage-Error, absolute-Percentage-Error, and root-mean-square Logarithmic-Error of the forecasting model are 0.54 ± 0.22, 1.51 ± 1.26, and 0.15 ± 0.07, respectively, indicating that the model performs well. Interpretation: Urological cancers exhibit an aging trend, with increased incidence rates among the population aged 55+ years, making prostate cancer the most burdensome subcategory. Moreover, urological cancer burden is imbalanced by age, sex, and province. Based on our findings, authorities and policymakers could refine or tailor population-specific health strategies, including promoting smoking cessation, weight reduction, and blood sugar control. Funding: Bill & Melinda Gates Foundation.
- Exploring the link between low germline mutational load and low breast cancer incidencePublication . Rueff, José; Rueff, Jose; Conde, João; Conde, João; Castro, Guilherme; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); Centre for Toxicogenomics and Human Health (ToxOmics); ElsevierThe study of cancer, its initiation, and its mechanisms of progression has been a focal point in science for more than a century. Despite controversies among scientists, there is a growing consensus to determine the moment when a cell gains the capacity to be transformed and whether this mechanism is to be attributed to germinal or somatic events, or possibly both. The case of the Xavante Indians is a beacon for this journey, pointing toward the importance of genetic diversity in shaping our approach to cancer research and treatment. As we incorporated these lessons into clinical practice, we embarked on a new era of personalized preventative healthcare strategies against cancer. Based on recent data, we comment on the low germinal mutational load and low cancer incidence. Statistical analyses reveal a significantly lower mutation burden in Xavante women compared to global populations (p < 0.0001), including rare deleterious variants in cancer-associated genes. Additionally, polygenic risk scores (PRS) for breast cancer are markedly lower in Xavante (mean PRS ∼35) compared to TCGA cohorts (∼80–90) (p < 0.0001). The absence of breast cancer cases in Xavante is statistically significant when compared to expected rates (p < 0.001), reinforcing the hypothesis of a protective genetic landscape.
- Translating nanomedicines from the lab to the clinicPublication . Herrmann, Inge; Li, Zhong Alan; Bahal, Raman; Conde, João; Conde, João; Centre for Toxicogenomics and Human Health (ToxOmics); Cell PressThe literature is replete with ingenious examples of nanomaterials engineered to address biomedical challenges. These materials may act as diagnostic agents, deliver active therapeutic agents, or intervene directly through a variety of modalities such as photothermal therapy. But the translation of such materials to the clinic remains uncommon.
- Autosomal Dominant Polycystic Kidney Disease Inflammation Biomarkers in the Tolvaptan EraPublication . Lapão, Tânia; Barata, Rui; Jorge, Cristina; Flores, Carlos; Calado, Joaquim; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); Centre for Toxicogenomics and Human Health (ToxOmics); MDPI - Multidisciplinary Digital Publishing InstituteWith the approval of tolvaptan as the first specific medicine for the treatment of rapidly progressive Autosomal Dominant Polycystic Kidney Disease (ADPKD), biomarker discovery has gained renewed interest as it is widely recognized that these will be crucial in clinical decision-making, serving as either prognostic or predictive tools. Since the marketing authorization was first issued in 2015 for ADPKD, tolvaptan has remained the sole pharmacological compound specifically targeting the disease. For ADPKD patients it is an invaluable medicine for retarding disease progression. Although the field of overall biomarker discovery and validation has been detailed in several publications, the role of inflammation remains largely overlooked in ADPKD. The current work aims to provide the reader with an updated review of inflammation biomarkers research in ADPKD, highlighting the role of urinary MCP-1 (monocyte chemoattractant protein-1) as the most promising tool.
- Technological challenges of biomembrane-coated top-down cancer nanotherapyPublication . Ravasco, João M.J.M.; Paiva-Santos, Ana Cláudia; Conde, João; Conde, João; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); Centre for Toxicogenomics and Human Health (ToxOmics); Nature ResearchCancer nanotherapy suffers from low-yield delivery that is imposed by tumour pathophysiological barriers. Top-down drug delivery strategies, including exosomes and cell membrane-coated particles, can improve safety and efficacy owing to the innate biointerfacial properties of these platforms. Here, we discuss the technological challenges that need to be overcome for their clinical implementation.