Yong Liu , Bowen Li , Run Yang , Chenxu Shang , Yang Bai , Bin Zheng , Liang Zhao
{"title":"Ultrasound-triggered lysosomal alkalinization to block autophagy in tumor therapy","authors":"Yong Liu , Bowen Li , Run Yang , Chenxu Shang , Yang Bai , Bin Zheng , Liang Zhao","doi":"10.1016/j.biomaterials.2025.123250","DOIUrl":null,"url":null,"abstract":"<div><div>Lysosomes play a crucial role in regulating cancer progression and drug resistance. However, there is a pressing need for the development of drugs that can safely and effectively modulate the pH of cancerous lysosomes in a controlled manner. In this study, we propose a novel strategy for lysosomal alkalinization triggered by piezoelectricity. Our findings indicate that the electrons generated by (BaTiO<sub>3</sub>/Zr/Ca) BCZT under sonication effectively alkalinize the lysosomes. Molecular dynamics simulations further demonstrate that alterations in lysosomal pH lead to modifications in the conformation of V-ATPase (proton pump), enhancing its interaction with sodium ions while partially excluding hydrogen ions from entering the lysosomes. This mechanism helps maintain lysosomal alkalization, resulting in reduced hydrolase activity and preventing the degradation of proteins and damaged organelles. The accumulation of nanoparticles within the lysosomes causes swelling and gradual destruction of the lysosomal membrane. Consequently, this lysosomal dysfunction hampers the fusion with autophagosomes, inhibiting autophagy in tumor cells and promoting apoptosis in various tumor types. Our strategy significantly inhibited tumor volume growth in mice during animal studies. In conclusion, our piezoelectric-triggered lysosomal alkalinization strategy holds promise for innovative breakthroughs in the treatment of multiple cancers.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"320 ","pages":"Article 123250"},"PeriodicalIF":12.8000,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biomaterials","FirstCategoryId":"5","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0142961225001693","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENGINEERING, BIOMEDICAL","Score":null,"Total":0}
引用次数: 0
Abstract
Lysosomes play a crucial role in regulating cancer progression and drug resistance. However, there is a pressing need for the development of drugs that can safely and effectively modulate the pH of cancerous lysosomes in a controlled manner. In this study, we propose a novel strategy for lysosomal alkalinization triggered by piezoelectricity. Our findings indicate that the electrons generated by (BaTiO3/Zr/Ca) BCZT under sonication effectively alkalinize the lysosomes. Molecular dynamics simulations further demonstrate that alterations in lysosomal pH lead to modifications in the conformation of V-ATPase (proton pump), enhancing its interaction with sodium ions while partially excluding hydrogen ions from entering the lysosomes. This mechanism helps maintain lysosomal alkalization, resulting in reduced hydrolase activity and preventing the degradation of proteins and damaged organelles. The accumulation of nanoparticles within the lysosomes causes swelling and gradual destruction of the lysosomal membrane. Consequently, this lysosomal dysfunction hampers the fusion with autophagosomes, inhibiting autophagy in tumor cells and promoting apoptosis in various tumor types. Our strategy significantly inhibited tumor volume growth in mice during animal studies. In conclusion, our piezoelectric-triggered lysosomal alkalinization strategy holds promise for innovative breakthroughs in the treatment of multiple cancers.
期刊介绍:
Biomaterials is an international journal covering the science and clinical application of biomaterials. A biomaterial is now defined as a substance that has been engineered to take a form which, alone or as part of a complex system, is used to direct, by control of interactions with components of living systems, the course of any therapeutic or diagnostic procedure. It is the aim of the journal to provide a peer-reviewed forum for the publication of original papers and authoritative review and opinion papers dealing with the most important issues facing the use of biomaterials in clinical practice. The scope of the journal covers the wide range of physical, biological and chemical sciences that underpin the design of biomaterials and the clinical disciplines in which they are used. These sciences include polymer synthesis and characterization, drug and gene vector design, the biology of the host response, immunology and toxicology and self assembly at the nanoscale. Clinical applications include the therapies of medical technology and regenerative medicine in all clinical disciplines, and diagnostic systems that reply on innovative contrast and sensing agents. The journal is relevant to areas such as cancer diagnosis and therapy, implantable devices, drug delivery systems, gene vectors, bionanotechnology and tissue engineering.