Full Text:   <2539>

Summary:  <103>

CLC number: 

On-line Access: 2025-06-23

Received: 2024-04-12

Revision Accepted: 2024-06-04

Crosschecked: 2025-09-23

Cited: 0

Clicked: 2005

Citations:  Bibtex RefMan EndNote GB/T7714

 ORCID:

Xiaodan HUANG

https://orcid.org/0009-0006-7783-243X

Yue FANG

https://orcid.org/0009-0003-4079-3332

Jie SONG

https://orcid.org/0009-0002-3453-7570

Yuanjing HAO

https://orcid.org/0009-0009-8840-7131

Yuanyuan CAI

https://orcid.org/0009-0007-8996-6790

Pengfei WEI

https://orcid.org/0000-0002-5786-6580

Na ZHANG

https://orcid.org/0009-0008-8121-2633

-   Go to

Article info.
Open peer comments

Journal of Zhejiang University SCIENCE B 2025 Vol.26 No.9 P.813-842

http://doi.org/10.1631/jzus.B2400186


Rescuing lysosomal/autophagic defects via nanoapproach: implications for lysosomal/autophagic defect-related diseases


Author(s):  Xiaodan HUANG, Yue FANG, Jie SONG, Yuanjing HAO, Yuanyuan CAI, Pengfei WEI, Na ZHANG

Affiliation(s):  School of Pharmacy, Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Yantai 264003, China; more

Corresponding email(s):   pfwei@bzmc.edu.cn, zhangna20@bzmc.edu.cn

Key Words:  Lysosome, Autophagy, Lysosomal/autophagic disfunction, Acidic nanoparticle, Transcription factor EB (TFEB), Dementia, Alzheimer's disease


Share this article to: More |Next Article >>>

Xiaodan HUANG, Yue FANG, Jie SONG, Yuanjing HAO, Yuanyuan CAI, Pengfei WEI, Na ZHANG. Rescuing lysosomal/autophagic defects via nanoapproach: implications for lysosomal/autophagic defect-related diseases[J]. Journal of Zhejiang University Science B, 2025, 26(9): 813-842.

@article{title="Rescuing lysosomal/autophagic defects via nanoapproach: implications for lysosomal/autophagic defect-related diseases",
author="Xiaodan HUANG, Yue FANG, Jie SONG, Yuanjing HAO, Yuanyuan CAI, Pengfei WEI, Na ZHANG",
journal="Journal of Zhejiang University Science B",
volume="26",
number="9",
pages="813-842",
year="2025",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B2400186"
}

%0 Journal Article
%T Rescuing lysosomal/autophagic defects via nanoapproach: implications for lysosomal/autophagic defect-related diseases
%A Xiaodan HUANG
%A Yue FANG
%A Jie SONG
%A Yuanjing HAO
%A Yuanyuan CAI
%A Pengfei WEI
%A Na ZHANG
%J Journal of Zhejiang University SCIENCE B
%V 26
%N 9
%P 813-842
%@ 1673-1581
%D 2025
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2400186

TY - JOUR
T1 - Rescuing lysosomal/autophagic defects via nanoapproach: implications for lysosomal/autophagic defect-related diseases
A1 - Xiaodan HUANG
A1 - Yue FANG
A1 - Jie SONG
A1 - Yuanjing HAO
A1 - Yuanyuan CAI
A1 - Pengfei WEI
A1 - Na ZHANG
J0 - Journal of Zhejiang University Science B
VL - 26
IS - 9
SP - 813
EP - 842
%@ 1673-1581
Y1 - 2025
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2400186


Abstract: 
The dysfunction of the lysosome and autophagy-lysosome system serves as a driving force for neurodegenerative diseases, metabolic disorders, inflammatory conditions, and other related diseases, closely influencing their onset and progression. Therefore, restoring the function of the lysosome or autophagy-lysosome system has become an increasingly crucial therapeutic strategy in disease management. In this review, we will introduce the lysosomal biogenesis, structure, and function, as well as the biological process of the autophagy-lysosome system. Various diseases closely associated with lysosomal/autophagic dysfunction are also reviewed, emphasizing the significance of targeting the function of the lysosome or autophagy-lysosome system in disease treatment. Finally, we focus on engineered nanomaterials that have the capabilities to restore the function of the lysosome or autophagy-lysosome system, and summarize different strategies and methods for achieving this goal. This review aims to elucidate the latest progress in the field of nanomedicine for lysosomal/autophagic defect-related diseases and inspire the development of innovative and clinically valuable nanomedicines.

通过纳米方法恢复溶酶体/自噬缺陷:对溶酶体/自噬缺陷相关疾病的意义

黄晓丹1, 方悦2, 宋杰1, 郝苑静1, 蔡园园1, 魏鹏飞1, 张娜1
1滨州医学院药学院, 山东省分子靶向智能诊疗技术创新中心, 中国烟台市, 264003
2浙江省中西医结合医院, 杭州市红十字会医院, 中国杭州市, 310003
摘要:溶酶体和自噬-溶酶体系统的功能障碍是神经退行性、代谢紊乱性、炎症性疾病和其他相关疾病的驱动力,影响疾病的发生和发展。因此,恢复溶酶体或自噬-溶酶体系统功能在上述疾病治疗中已成为日益重要的策略。本文对溶酶体的生物发生、结构和功能,以及自噬-溶酶体系统的生物学过程展开介绍;综述了与溶酶体/自噬功能障碍密切相关的各种疾病,揭示调节溶酶体或自噬-溶酶体系统功能在疾病治疗中的重要性;重点探讨了能够恢复溶酶体或自噬-溶酶体系统功能的工程化纳米材料,并对实现这一目标的不同策略和方法进行总结。本文旨在阐明纳米医学领域治疗溶酶体/自噬缺陷相关疾病的最新进展,并推动具有临床价值的创新纳米药物的开发。

关键词:溶酶体;自噬;溶酶体/自噬功能障碍;酸性纳米颗粒;转录因子EB(TFEB);痴呆;阿尔兹海默症

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

Reference

[1]AbokyiS, Ghartey-KwansahG, TseDYY, 2023. TFEB is a central regulator of the aging process and age-related diseases. Ageing Res Rev, 89:101985.

[2]AhmadiA, ArgulianE, LeipsicJ, et al., 2019. From subclinical atherosclerosis to plaque progression and acute coronary events: JACC state-of-the-art review. J Am Coll Cardiol, 74(12):1608-1617.

[3]AmanY, Schmauck-MedinaT, HansenM, et al., 2021. Autophagy in healthy aging and disease. Nat Aging, 1:‍634-650.

[4]AndersonJM, ShiveMS, 1997. Biodegradation and biocompatibility of PLA and PLGA microspheres. Adv Drug Delivery Rev, 28:5-24.

[5]AntonucciL, FagmanJB, KimJY, et al., 2015. Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress. Proc Natl Acad Sci USA, 112(45):E6166-E6174.

[6]ArdanT, BaxaM, LevinskáB, et al., 2020. Transgenic minipig model of Huntington’s disease exhibiting gradually progressing neurodegeneration. Dis Models Mech, 13(2):dmm041319.

[7]ArotcarenaML, SoriaFN, CunhaA, et al., 2022. Acidic nanoparticles protect against α‍-synuclein-induced neurodegeneration through the restoration of lysosomal function. Aging Cell, 21(4):e13584.

[8]AssaliEA, ShlomoD, ZengJJ, et al., 2019. Nanoparticle-mediated lysosomal reacidification restores mitochondrial turnover and function in β cells under lipotoxicity. FASEB J, 33(3):4154-4165.

[9]AyyildizD, BergonzoniG, MonzianiA, et al., 2023. CAG repeat expansion in the Huntington’s disease gene shapes linear and circular RNAs biogenesis. PLoS Genet, 19(10):e1010988.

[10]BagshawRD, MahuranDJ, CallahanJW, 2005. A proteomic analysis of lysosomal integral membrane proteins reveals the diverse composition of the organelle. Mol Cell Proteomics, 4(2):133-143.

[11]BallabioA, BonifacinoJS, 2020. Lysosomes as dynamic regulators of cell and organismal homeostasis. Nat Rev Mol Cell Biol, 21(2):101-118.

[12]BaltazarGC, GuhaS, LuWN, et al., 2012. Acidic nanoparticles are trafficked to lysosomes and restore an acidic lysosomal pH and degradative function to compromised ARPE-19 cells. PLoS ONE, 7(12):e49635.

[13]Ben-ShlomoY, DarweeshS, Llibre-GuerraJ, et al., 2024. The epidemiology of Parkinson’s disease. Lancet, 403(10423):283-292.

[14]BourdenxM, DanielJ, GeninE, et al., 2016. Nanoparticles restore lysosomal acidification defects: implications for Parkinson and other lysosomal-related diseases. Autophagy, 12(3):472-483.

[15]BoyaP, 2012. Lysosomal function and dysfunction: mechanism and disease. Antioxid Redox Signaling, 17(5):‍‍766-774.

[16]BraulkeT, CaretteJE, PalmW, 2024. Lysosomal enzyme trafficking: from molecular mechanisms to human diseases. Trends Cell Biol, 34(3):198-210.

[17]BrouillardM, BarthélémyP, DehayB, et al., 2021. Nucleolipid acid-based nanocarriers restore neuronal lysosomal acidification defects. Front Chem, 9:736554.

[18]BrouillardM, KinetR, JoyeuxM, et al., 2023. Modulating lysosomal pH through innovative multimerized succinic acid-based nucleolipid derivatives. Bioconjugate Chem, 34(3):572-580.

[19]BruijnLI, HouseweartMK, KatoS, et al., 1998. Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1. Science, 281(5384):1851-1854.

[20]CaiXS, SheMQ, XuMY, et al., 2018. GLP-1 treatment protects endothelial cells from oxidative stress-induced autophagy and endothelial dysfunction. Int J Biol Sci, 14(12):1696-1708.

[21]CalabresiP, di LazzaroG, MarinoG, et al., 2023. Advances in understanding the function of alpha-synuclein: implications for Parkinson’s disease. Brain, 146(9):3587-3597.

[22]CarlssonSR, FukudaM, 1992. The lysosomal membrane glycoprotein lamp-1 is transported to lysosomes by two alternative pathways. Arch Biochem Biophys, 296(2):630-639.

[23]CeccarigliaS, CargnoniA, SiliniAR, et al., 2020. Autophagy: a potential key contributor to the therapeutic action of mesenchymal stem cells. Autophagy, 16(1):28-37.

[24]ChapelA, Kieffer-JaquinodS, SagnéC, et al., 2013. An extended proteome map of the lysosomal membrane reveals novel potential transporters. Mol Cell Proteomics, 12(6):1572-1588.

[25]ChattopadhyayM, ValentineJS, 2009. Aggregation of copper–zinc superoxide dismutase in familial and sporadic ALS. Antioxid Redox Signaling, 11(7):1603-1614.

[26]ChenHY, YeTW, HuFQ, et al., 2023. Urchin-like ceria nanoparticles for enhanced gene therapy of osteoarthritis. Sci Adv, 9(24):eadf0988.

[27]ChenS, ZhangXJ, SongL, et al., 2012. Autophagy dysregulation in amyotrophic lateral sclerosis. Brain Pathol, 22:110-116.

[28]ChenX, PanditS, ShiL, et al., 2023. Graphene oxide attenuates toxicity of amyloid-β aggregates in yeast by promoting disassembly and boosting cellular stress response. Adv Funct Mater, 33(45):2304053.

[29]ChenYK, ZengA, HeSM, et al., 2021. Autophagy-related genes in atherosclerosis. J Healthc Eng, 2021:6402206.

[30]ChithraniBD, ChanWCW, 2007. Elucidating the mechanism of cellular uptake and removal of protein-coated gold nanoparticles of different sizes and shapes. Nano Lett, 7(6):1542-1550.

[31]ChithraniBD, GhazaniAA, ChanWCW, 2006. Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells. Nano Lett, 6(4):662-668.

[32]ChoWS, DuffinR, HowieSEM, et al., 2011. Progressive severe lung injury by zinc oxide nanoparticles; the role of Zn2+ dissolution inside lysosomes. Part Fibre Toxicol, 8:27.

[33]ChoiI, WangMH, YooS, et al., 2023. Autophagy enables microglia to engage amyloid plaques and prevents microglial senescence. Nat Cell Biol, 25(7):963-974.

[34]ChuFX, LiK, LiXL, et al., 2021. Graphene oxide ameliorates the cognitive impairment through inhibiting PI3K/Akt/mTOR pathway to induce autophagy in AD mouse model. Neurochem Res, 46(2):309-325.

[35]CunhaA, PrévotG, MousliY, et al., 2020. Synthesis and intracellular uptake of rhodamine–‍nucleolipid conjugates into a nanoemulsion vehicle. ACS Omega, 5(11):5815-5823.

[36]dal CantoMC, GurneyME, 1995. Neuropathological changes in two lines of mice carrying a transgene for mutant human Cu, Zn SOD, and in mice overexpressing wild type human SOD: a model of familial amyotrophic lateral sclerosis (FALS). Brain Res, 676:25-40.

[37]DavoodyS, TaeiAA, KhodabakhshP, et al., 2024. mTOR signaling and Alzheimer’s disease: what we know and where we are? CNS Neurosci Ther, 30(4):e14463.

[38]DehayB, BovéJ, Rodríguez-MuelaN, et al., 2010. Pathogenic lysosomal depletion in Parkinson’s disease. J Neurosci, 30(37):12535-12544.

[39]DevadigaSJ, BharateSS, 2022. Recent developments in the management of Huntington’s disease. Bioorg Chem, 120:105642.

[40]DiakopoulosKN, LesinaM, WörmannS, et al., 2015. Impaired autophagy induces chronic atrophic pancreatitis in mice via sex-and nutrition-dependent processes. Gastroenterology, 148(3):626-638.e17.

[41]DikicI, ElazarZ, 2018. Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol, 19(6):349-364.

[42]EskelinenEL, 2006. Roles of LAMP-1 and LAMP-2 in lysosome biogenesis and autophagy. Mol Aspects Med, 27(5-6):495-502.

[43]EzquerroS, MochaF, FrühbeckG, et al., 2019. Ghrelin reduces TNF-‍α‍-induced human hepatocyte apoptosis, autophagy, and pyroptosis: role in obesity-associated NAFLD. J Clin Endocrinol Metab, 104(1):21-37.

[44]FangEF, Scheibye-KnudsenM, BraceLE, et al., 2014. Defective mitophagy in XPA via PARP-1 hyperactivation and NAD+/SIRT1 reduction. Cell, 157(4):882-896.

[45]FangEF, KassahunH, CroteauDL, et al., 2016. NAD+ replenishment improves lifespan and healthspan in ataxia telangiectasia models via mitophagy and DNA repair. Cell Metab, 24(4):566-581.

[46]FangEF, HouYJ, PalikarasK, et al., 2019. Mitophagy inhibits amyloid-‍β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease. Nat Neurosci, 22(3):401-412.

[47]FangEF, XieCL, SchenkelJA, et al., 2020. A research agenda for ageing in China in the 21st century (2nd edition): focusing on basic and translational research, long-term care, policy and social networks. Ageing Res Rev, 64:101174.

[48]FeldmanEL, GoutmanSA, PetriS, et al., 2022. Amyotrophic lateral sclerosis. Lancet, 400(10360):1363-1380.

[49]Frendo-CumboS, TokarzVL, BilanPJ, et al., 2021. Communication between autophagy and insulin action: at the crux of insulin action-insulin resistance? Front Cell Dev Biol, 9:708431.

[50]FukuoY, YamashinaS, SonoueH, et al., 2014. Abnormality of autophagic function and cathepsin expression in the liver from patients with non-alcoholic fatty liver disease. Hepatol Res, 44(9):1026-1036.

[51]GePP, GaoMX, DuJ, et al., 2021. Downregulation of microRNA-512-3p enhances the viability and suppresses the apoptosis of vascular endothelial cells, alleviates autophagy and endoplasmic reticulum stress as well as represses atherosclerotic lesions in atherosclerosis by adjusting spliced/unspliced ratio of X-box binding protein 1 (XBP-1S/XBP-1U). Bioengineered, 12(2):12469-12481.

[52]SAISMGhazali, FatimahI, ZamilZN, et al., 2023. Graphene quantum dots: a comprehensive overview. Open Chem, 21:20220285.

[53]GissotA, CamploM, GrinstaffMW, et al., 2008. Nucleoside, nucleotide and oligonucleotide based amphiphiles: a successful marriage of nucleic acids with lipids. Org Biomol Chem, 6(8):1324-1333.

[54]GriffeyCJ, YamamotoA, 2022. Macroautophagy in CNS health and disease. Nat Rev Neurosci, 23(7):411-427.

[55]GrosF, MullerS, 2023. The role of lysosomes in metabolic and autoimmune diseases. Nat Rev Nephrol, 19(6):366-383.

[56]GukovskayaAS, GukovskyI, 2012. Autophagy and pancreatitis. Am J Physiol-Gastrointest Liver Physiol, 303(9):‍G993-G1003.

[57]GuoYL, DuanWJ, LuDH, et al., 2021. Autophagy-dependent removal of α‍-synuclein: a novel mechanism of GM1 ganglioside neuroprotection against Parkinson’s disease. Acta Pharmacol Sin, 42(4):518-528.

[58]HämälistöS, JäätteläM, 2016. Lysosomes in cancer—living on the edge (of the cell). Curr Opin Cell Biol, 39:69-76.

[59]HamburgNM, CreagerMA, 2017. Pathophysiology of intermittent claudication in peripheral artery disease. Circ J, 81(3):281-289.

[60]HeJL, LiuJY, HuangY, et al., 2021. Oxidative stress, inflammation, and autophagy: potential targets of mesenchymal stem cells-based therapies in ischemic stroke. Front Neurosci, 15:641157.

[61]HeLN, ZhaoJT, WangLM, et al., 2021. Using nano-selenium to combat coronavirus disease 2019 (COVID-19)? Nano Today, 36:101037.

[62]HeLZ, HuangGN, LiuHX, et al., 2020. Highly bioactive zeolitic imidazolate framework-8‍–‍capped nanotherapeutics for efficient reversal of reperfusion-induced injury in ischemic stroke. Sci Adv, 6(12):eaay9751.

[63]HerringtonW, LaceyB, SherlikerP, et al., 2016. Epidemiology of atherosclerosis and the potential to reduce the global burden of atherothrombotic disease. Circ Res, 118(4):‍535-546.

[64]HollandLKK, NielsenIØ, MaedaK, et al., 2020. Snapshot: lysosomal functions. Cell, 181(3):748-748.e1.

[65]HongSE, AnJH, YuSL, et al., 2020. Ceria-zirconia antioxidant nanoparticles attenuate hypoxia-induced acute kidney injury by restoring autophagy flux and alleviating mitochondrial damage. J Biomed Nanotechnol, 16(7):1144-1159.

[66]HoweCL, GrangerBL, HullM, et al., 1988. Derived protein sequence, oligosaccharides, and membrane insertion of the 120-kDa lysosomal membrane glycoprotein (lgp120): identification of a highly conserved family of lysosomal membrane glycoproteins. Proc Natl Acad Sci USA, 85(20):7577-7581.

[67]HuL, LiuY, WangS, 2018. Stem cell-based tooth and periodontal regeneration. Oral Dis, 24(5):696-705.

[68]HuXD, LinR, ZhangCQ, et al., 2023. Nano-selenium alleviates cadmium-induced mouse leydig cell injury, via the inhibition of reactive oxygen species and the restoration of autophagic flux. Reprod Sci, 30(6):1808-1822.

[69]HuangYY, YuMX, ZhengJ, 2023. Proximal tubules eliminate endocytosed gold nanoparticles through an organelle-extrusion-mediated self-renewal mechanism. Nat Nanotechnol, 18(6):637-646.

[70]IlievaH, VullagantiM, KwanJ, 2023. Advances in molecular pathology, diagnosis, and treatment of amyotrophic lateral sclerosis. BMJ, 383:e075037.

[71]InamiY, YamashinaS, IzumiK, et al., 2011. Hepatic steatosis inhibits autophagic proteolysis via impairment of autophagosomal acidification and cathepsin expression. Biochem Biophys Res Commun, 412(4):618-625.

[72]IyaswamyA, ThakurA, GuanXJ, et al., 2023. Fe65-engineered neuronal exosomes encapsulating corynoxine-B ameliorate cognition and pathology of Alzheimer’s disease. Signal Transduct Target Ther, 8:404.

[73]JanvierK, BonifacinoJS, 2005. Role of the endocytic machinery in the sorting of lysosome-associated membrane proteins. Mol Biol Cell, 16(9):4231-4242.

[74]JeongJK, LeeYJ, JeongSY, et al., 2017. Autophagic flux induced by graphene oxide has a neuroprotective effect against human prion protein fragments. Int J Nanomed, 12:8143-8158.

[75]JeromeWG, CoxBE, GriffinEE, et al., 2008. Lysosomal cholesterol accumulation inhibits subsequent hydrolysis of lipoprotein cholesteryl ester. Microsc Microanal, 14(2):138-149.

[76]JinPP, WeiPF, ZhangYJ, et al., 2016. Autophagy-mediated clearance of ubiquitinated mutant huntingtin by graphene oxide. Nanoscale, 8(44):18740-18750.

[77]JohnsonAA, CuellarTL, 2023. Glycine and aging: evidence and mechanisms. Ageing Res Rev, 87:101922.

[78]KangI, YooJM, KimD, et al., 2021. Graphene quantum dots alleviate impaired functions in Niemann-Pick disease type C in vivo. Nano Lett, 21(5):2339-2346.

[79]KashimaJ, Shintani-IshidaK, NakajimaM, et al., 2014. Immunohistochemical study of the autophagy marker microtubule-associated protein 1 light chain 3 in normal and steatotic human livers. Hepatol Res, 44(7):779-787.

[80]KaurSJ, McKeownSR, RashidS, 2016. Mutant SOD1 mediated pathogenesis of amyotrophic lateral sclerosis. Gene, 577(2):109-118.

[81]KegelKB, KimM, SappE, et al., 2000. Huntingtin expression stimulates endosomal‍–‍lysosomal activity, endosome tubulation, and autophagy. J Neurosci, 20(19):7268-7278.

[82]KimB, KimG, JeonS, et al., 2023. Zinc oxide nanoparticles trigger autophagy-mediated cell death through activating lysosomal TRPML1 in normal kidney cells. Toxicol Rep, 10:529-536.

[83]KimD, YooJM, HwangH, et al., 2018. Graphene quantum dots prevent α‍-synucleinopathy in Parkinson’s disease. Nat Nanotechnol, 13(9):812-818.

[84]KimYG, LeeY, LeeN, et al., 2024. Ceria-based therapeutic antioxidants for biomedical applications. Adv Mater, 36(10):2210819.

[85]KogaH, KaushikS, CuervoAM, 2010. Altered lipid content inhibits autophagic vesicular fusion. FASEB J, 24(8):3052-3065.

[86]KoleiniN, KardamiE, 2017. Autophagy and mitophagy in the context of doxorubicin-induced cardiotoxicity. Oncotarget, 8(28):46663-46680.

[87]KornfeldS, MellmanI, 1989. The biogenesis of lysosomes. Ann Rev Cell Biol, 5:483-525.

[88]KrachF, StemickJ, BoerstlerT, et al., 2022. An alternative splicing modulator decreases mutant HTT and improves the molecular fingerprint in Huntington’s disease patient neurons. Nat Commun, 13:6797.

[89]KumariA, YadavSK, YadavSC, 2010. Biodegradable polymeric nanoparticles based drug delivery systems. Colloids Surf B Biointerfaces, 75:1-18.

[90]KyleS, SahaS, 2014. Nanotechnology for the detection and therapy of stroke. Adv Healthcare Mater, 3(11):1703-1720.

[91]LabrijnAF, MeestersJI, BunceM, et al., 2017. Efficient generation of bispecific murine antibodies for pre-clinical investigations in syngeneic rodent models. Sci Rep, 7:2476.

[92]LasG, SeradaSB, WikstromJD, et al., 2011. Fatty acids suppress autophagic turnover in β‍-cells. J Biol Chem, 286(49):42534-42544.

[93]LebeaupinC, ValléeD, HazariY, et al., 2018. Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease. J Hepatol, 69(4):927-947.

[94]LeeJ, SungKW, BaeEJ, et al., 2023. Targeted degradation of α-synuclein aggregates in Parkinson’s disease using the AUTOTAC technology. Mol Neurodegener, 18:41.

[95]LeeJH, NixonRA, 2022. Autolysosomal acidification failure as a primary driver of Alzheimer disease pathogenesis. Autophagy, 18(11):2763-2764.

[96]LeeJH, YangDS, GoulbourneCN, et al., 2022. Faulty autolysosome acidification in Alzheimer’s disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques. Nat Neurosci, 25(6):688-701.

[97]LeidalAM, LevineB, DebnathJ, 2018. Autophagy and the cell biology of age-related disease. Nat Cell Biol, 20(12):1338-1348.

[98]LescatL, HerpinA, MourotB, et al., 2018. CMA restricted to mammals and birds: myth or reality? Autophagy, 14(7):1267-1270.

[99]LevineB, KroemerG, 2019. Biological functions of autophagy genes: a disease perspective. Cell, 176(1-2):11-42.

[100]LiDL, WangZV, DingGQ, et al., 2016. Doxorubicin blocks cardiomyocyte autophagic flux by inhibiting lysosome acidification. Circulation, 133(17):1668-1687.

[101]LiMC, SalaV, de SantisMC, et al., 2018. Phosphoinositide 3-kinase gamma inhibition protects from anthracycline cardiotoxicity and reduces tumor growth. Circulation, 138(7):696-711.

[102]LiQ, YangGW, LiJL, et al., 2020. Stem cell therapies for periodontal tissue regeneration: a network meta-analysis of preclinical studies. Stem Cell Res Ther, 11:427.

[103]LiSL, ZhangCQ, CaoWP, et al., 2015. Anchoring effects of surface chemistry on gold nanorods: modulating autophagy. J Mater Chem B, 3(16):3324-3330.

[104]LiXL, LiK, ChuFX, et al., 2020. Graphene oxide enhances β‍‍-amyloid clearance by inducing autophagy of microglia and neurons. Chem-Biol Interact, 325:109126.

[105]LiZY, WangC, WangZY, et al., 2019. Allele-selective lowering of mutant HTT protein by HTT‍–‍LC3 linker compounds. Nature, 575:203-209.

[106]LinL, ZhangMX, ZhangL, et al., 2022. Autophagy, pyroptosis, and ferroptosis: new regulatory mechanisms for atherosclerosis. Front Cell Dev Biol, 9:809955.

[107]LitwiniukA, JuszczakGR, StankiewiczAM, et al., 2023. The role of glial autophagy in Alzheimer’s disease. Mol Psychiatry, 28(11):4528-4539.

[108]LiuHY, HanJM, CaoSY, et al., 2009. Hepatic autophagy is suppressed in the presence of insulin resistance and hyperinsulinemia. J Biol Chem, 284(45):31484-31492.

[109]LiuL, XuQ, ZhangL, et al., 2021. Fe3O4 magnetic nanoparticles ameliorate albumin-induced tubulointerstitial fibrosis by autophagy related to Rab7. Colloids Surf B Biointerfaces, 198:111470.

[110]LiuW, WangG, WangZW, et al., 2022. Repurposing small-molecule drugs for modulating toxic protein aggregates in neurodegenerative diseases. Drug Discovery Today, 27(7):1994-2007.

[111]LiuY, WangXN, WangJ, et al., 2016. Graphene oxide attenuates the cytotoxicity and mutagenicity of PCB 52 via activation of genuine autophagy. Environ Sci Technol, 50(6):3154-3164.

[112]López-OtínC, BlascoMA, PartridgeL, et al., 2023. Hallmarks of aging: an expanding universe. Cell, 186(2):‍243-278.

[113]LouGF, PalikarasK, LautrupS, et al., 2020. Mitophagy and neuroprotection. Trends Mol Med, 26(1):8-20.

[114]MaNN, LiuPD, HeNY, et al., 2017. Action of gold nanospikes-based nanoradiosensitizers: cellular internalization, radiotherapy, and autophagy. ACS Appl Mater Interfaces, 9(37):31526-31542.

[115]MaXW, WuYY, JinSB, et al., 2011. Gold nanoparticles induce autophagosome accumulation through size-dependent nanoparticle uptake and lysosome impairment. ACS Nano, 5(11):8629-8639.

[116]MahapatroA, SinghDK, 2011. Biodegradable nanoparticles are excellent vehicle for site directed in-vivo delivery of drugs and vaccines. J Nanobiotechnol, 9:55.

[117]MahmoudiM, AkhavanO, GhavamiM, et al., 2012. Graphene oxide strongly inhibits amyloid beta fibrillation. Nanoscale, 4(23):7322-7325.

[118]MakSK, McCormackAL, Manning-BoğAB, et al., 2010. Lysosomal degradation of α‍-synuclein in vivo. J Biol Chem, 285(18):13621-13629.

[119]MamaisA, WallingsR, RochaEM, 2023. Disease mechanisms as subtypes: lysosomal dysfunction in the endolysosomal Parkinson’s disease subtype. Handb Clin Neurol, 193:33-51.

[120]MareninovaOA, HermannK, FrenchSW, et al., 2009. Impaired autophagic flux mediates acinar cell vacuole formation and trypsinogen activation in rodent models of acute pancreatitis. J Clin Invest, 119(11):3340-3355.

[121]MareninovaOA, SendlerM, MallaSR, et al., 2015. Lysosome-associated membrane proteins (LAMP) maintain pancreatic acinar cell homeostasis: LAMP-2‍–‍deficient mice develop pancreatitis. Cell Mol Gastroenterol Hepatol, 1(6):678-694.

[122]MariM, BujnyMV, ZeuschnerD, et al., 2008. SNX1 defines an early endosomal recycling exit for sortilin and mannose 6-phosphate receptors. Traffic, 9(3):380-393.

[123]MartensS, FracchiollaD, 2020. Activation and targeting of ATG8 protein lipidation. Cell Discov, 6:23.

[124]MartinaJA, ChenY, GucekM, et al., 2012. MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy, 8(6):‍903-914.

[125]Martinez-VicenteM, TalloczyZ, WongE, et al., 2010. Cargo recognition failure is responsible for inefficient autophagy in Huntington’s disease. Nat Neurosci, 13(5):567-576.

[126]MattsonMP, ArumugamTV, 2018. Hallmarks of brain aging: adaptive and pathological modification by metabolic states. Cell Metab, 27(6):1176-1199.

[127]MaysingerD, GranER, BertorelleF, et al., 2020. Gold nanoclusters elicit homeostatic perturbations in glioblastoma cells and adaptive changes of lysosomes. Theranostics, 10(4):1633-1648.

[128]McColganP, TabriziSJ, 2018. Huntington’s disease: a clinical review. Eur J Neurol, 25(1):24-34.

[129]MenghiniR, CasagrandeV, MarinoA, et al., 2014. MiR-216a: a link between endothelial dysfunction and autophagy. Cell Death Dis, 5:e1029.

[130]MiceliC, LeriM, StefaniM, et al., 2023. Autophagy-related proteins: potential diagnostic and prognostic biomarkers of aging-related diseases. Ageing Res Rev, 89:101967.

[131]MirSUR, GeorgeNM, ZahoorL, et al., 2015. Inhibition of autophagic turnover in β‍-cells by fatty acids and glucose leads to apoptotic cell death. J Biol Chem, 290(10):‍6071-6085.

[132]MizushimaN, KomatsuM, 2011. Autophagy: renovation of cells and tissues. Cell, 147(4):728-741.

[133]MooreKJ, SheedyFJ, FisherEA, 2013. Macrophages in atherosclerosis: a dynamic balance. Nat Rev Immunol, 13(10):709-721.

[134]MorrisHR, SpillantiniMG, SueCM, et al., 2024. The pathogenesis of Parkinson’s disease. Lancet, 403(10423):‍293-304.

[135]MuhammadP, HanifS, LiJY, et al., 2022. Carbon dots supported single Fe atom nanozyme for drug-resistant glioblastoma therapy by activating autophagy-lysosome pathway. Nano Today, 45:101530.

[136]NowellJ, BluntE, GuptaD, et al., 2023. Antidiabetic agents as a novel treatment for Alzheimer’s and Parkinson’s disease. Ageing Res Rev, 89:101979.

[137]PanL, FeiginA, 2021. Huntington’s disease: new frontiers in therapeutics. Curr Neurol Neurosci Rep, 21(3):10.

[138]PartridgeL, DeelenJ, SlagboomPE, 2018. Facing up to the global challenges of ageing. Nature, 561:45-56.

[139]ParzychKR, KlionskyDJ, 2014. An overview of autophagy: morphology, mechanism, and regulation. Antioxid Redox Signaling, 20(3):460-473.

[140]PayneT, BurgessT, BradleyS, et al., 2024. Multimodal assessment of mitochondrial function in Parkinson’s disease. Brain, 147(1):267-280.

[141]PeiXY, LiuDK, LiJJ, et al., 2023. TFEB coordinates autophagy and pyroptosis as hepatotoxicity responses to ZnO nanoparticles. Sci Total Environ, 865:161242.

[142]PeshkovaIO, SchaeferG, KoltsovaEK, 2016. Atherosclerosis and aortic aneurysm – is inflammation a common denominator? FEBS J, 283(9):1636-1652.

[143]PirasA, CollinL, GrüningerF, et al., 2016. Autophagic and lysosomal defects in human tauopathies: analysis of post-mortem brain from patients with familial Alzheimer disease, corticobasal degeneration and progressive supranuclear palsy. Acta Neuropathol Commun, 4:22.

[144]PoppL, SegatoriL, 2019. Zinc oxide particles induce activation of the lysosome–autophagy system. ACS Omega, 4(1):573-581.

[145]PresterudR, DengWH, WennerströmAB, et al., 2024. Long-term nicotinamide riboside use improves coordination and eye movements in ataxia telangiectasia. Mov Disord, 39(2):360-369.

[146]PrévotG, SoriaFN, ThiolatML, et al., 2018. Harnessing lysosomal pH through PLGA nanoemulsion as a treatment of lysosomal-related neurodegenerative diseases. Bioconjugate Chem, 29(12):4083-4089.

[147]PrietoGA, CotmanCW, 2022. Early bioenergetic and autophagy impairments at the Parkinson’s disease synapse. Brain, 145(6):1877-1879.

[148]QueirozA, Albuquerque-SouzaE, GasparoniLM, et al., 2021. Therapeutic potential of periodontal ligament stem cells. World J Stem Cells, 13(6):605-618.

[149]RenXQ, ChenYT, PengHB, et al., 2018. Blocking autophagic flux enhances iron oxide nanoparticle photothermal therapeutic efficiency in cancer treatment. ACS Appl Mater Interfaces, 10(33):27701-27711.

[150]RiccardiC, MusumeciD, IraceC, et al., 2017. RuIII complexes for anticancer therapy: the importance of being nucleolipidic. Eur J Org Chem, 2017(7):1100-1119.

[151]RobberechtW, PhilipsT, 2013. The changing scene of amyotrophic lateral sclerosis. Nat Rev Neurosci, 14(4):248-264.

[152]RubinszteinDC, GestwickiJE, MurphyLO, et al., 2007. Potential therapeutic applications of autophagy. Nat Rev Drug Discov, 6(4):304-312.

[153]SaftigP, KlumpermanJ, 2009. Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function. Nat Rev Mol Cell Biol, 10(9):623-635.

[154]SantinY, FormosoK, HaidarF, et al., 2023. Inhalation of acidic nanoparticles prevents doxorubicin cardiotoxicity through improvement of lysosomal function. Theranostics, 13(15):5435-5451.

[155]SardielloM, PalmieriM, Di RonzaA, et al., 2009. A gene network regulating lysosomal biogenesis and function. Science, 325(5939):473-477.

[156]Schmauck-MedinaT, MolièreA, LautrupS, et al., 2022. New hallmarks of ageing: a 2022 Copenhagen ageing meeting summary. Aging, 14(16):6829-6839.

[157]SchützmannMP, HaseckeF, BachmannS, et al., 2021. Endo-lysosomal Aβ concentration and pH trigger formation of Aβ oligomers that potently induce Tau missorting. Nat Commun, 12:4634.

[158]SeoBM, MiuraM, GronthosS, et al., 2004. Investigation of multipotent postnatal stem cells from human periodontal ligament. Lancet, 364(9429):149-155.

[159]SettembreC, PereraRM, 2024. Lysosomes as coordinators of cellular catabolism, metabolic signalling and organ physiology. Nat Rev Mol Cell Biol, 25(3):223-245.

[160]SettembreC, de CegliR, MansuetoG, et al., 2013. TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. Nat Cell Biol, 15(6):647-658.

[161]ShaoBZ, HanBZ, ZengYX, et al., 2016. The roles of macrophage autophagy in atherosclerosis. Acta Pharmacol Sin, 37(2):150-156.

[162]ShenYR, XiaoYQ, ZhangS, et al., 2020. Fe3O4 nanoparticles attenuated Salmonella infection in chicken liver through reactive oxygen and autophagy via PI3K/Akt/mTOR signaling. Front Physiol, 10:1580.

[163]ShimobayashiM, HallMN, 2014. Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat Rev Mol Cell Biol, 15(3):155-162.

[164]SimeoneL, MangiapiaG, IraceC, et al., 2011. Nucleolipid nanovectors as molecular carriers for potential applications in drug delivery. Mol BioSyst, 7(11):3075-3086.

[165]SongWS, LeeSS, SaviniM, et al., 2014. Ceria nanoparticles stabilized by organic surface coatings activate the lysosome-autophagy system and enhance autophagic clearance. ACS Nano, 8(10):10328-10342.

[166]SunYN, LiMJ, ZhaoDF, et al., 2020. Lysosome activity is modulated by multiple longevity pathways and is important for lifespan extension in C. elegans. eLife, 9:e55745.

[167]Swastika, ChaturvediS, KaulA, et al., 2019. Evaluation of BBB permeable nucleolipid (NLDPU): a di-C15-ketalised palmitone appended uridine as neuro-tracer for SPECT. Int J Pharm, 565:269-282.

[168]TisiA, FlatiV, MonacheSD, et al., 2020. Nanoceria particles are an eligible candidate to prevent age-related macular degeneration by inhibiting retinal pigment epithelium cell death and autophagy alterations. Cells, 9(7):1617.

[169]TrudeauKM, ColbyAH, ZengJL, et al., 2016. Lysosome acidification by photoactivated nanoparticles restores autophagy under lipotoxicity. J Cell Biol, 214(1):25-34.

[170]TuHY, YuanBS, HouXO, et al., 2021. α‍-Synuclein suppresses microglial autophagy and promotes neurodegeneration in a mouse model of Parkinson’s disease. Aging Cell, 20(12):e13522.

[171]UenoT, KomatsuM, 2017. Autophagy in the liver: functions in health and disease. Nat Rev Gastroenterol Hepatol, 14(3):170-184.

[172]van TielFH, BoereWA, HarmsenT, et al., 1985. Determination of inhibitory concentrations of antiviral agents in cell culture by use of an enzyme immunoassay with virus-specific, peroxidase-labeled monoclonal antibodies. Antimicrob Agents Chemother, 27(5):802-805.

[173]VeverováK, LaczóJ, KatonováA, et al., 2024. Alterations of human CSF and serum-based mitophagy biomarkers in the continuum of Alzheimer disease. Autophagy, 20(8):1868-1878.

[174]WallingsRL, HumbleSW, WardME, et al., 2019. Lysosomal dysfunction at the centre of Parkinson’s disease and frontotemporal dementia/amyotrophic lateral sclerosis. Trends Neurosci, 42(12):899-912.

[175]WanHY, ChenJL, ZhuXZ, et al., 2018. Titania-coated gold nano-bipyramids for blocking autophagy flux and sensitizing cancer cells to proteasome inhibitor-induced death. Adv Sci, 5(3):1700585.

[176]WangL, WangZJ, LiXM, et al., 2018. Deciphering active biocompatibility of iron oxide nanoparticles from their intrinsic antagonism. Nano Res, 11(5):2746-2755.

[177]WangQ, WangY, LiSP, et al., 2023. PACAP‍–‍Sirtuin3 alleviates cognitive impairment through autophagy in Alzheimer’s disease. Alzheimers Res Ther, 15:184.

[178]WangY, WuQ, AnandBG, et al., 2020. Significance of cytosolic cathepsin D in Alzheimer’s disease pathology: protective cellular effects of PLGA nanoparticles against β‍-amyloid-toxicity. Neuropathol Appl Neurobiol, 46(7):686-706.

[179]WeiPF, ZhangL, NethiSK, et al., 2014. Accelerating the clearance of mutant huntingtin protein aggregates through autophagy induction by europium hydroxide nanorods. Biomaterials, 35(3):899-907.

[180]WeiPF, JinPP, BaruiAK, et al., 2015. Differential ERK activation during autophagy induced by europium hydroxide nanorods and trehalose: maximum clearance of huntingtin aggregates through combined treatment. Biomaterials, 73:160-174.

[181]WengQJ, SunH, FangCY, et al., 2021. Catalytic activity tunable ceria nanoparticles prevent chemotherapy-induced acute kidney injury without interference with chemotherapeutics. Nat Commun, 12:1436.

[182]WilsonN, KatauraT, KorsgenME, et al., 2023. The autophagy–NAD axis in longevity and disease. Trends Cell Biol, 33(9):788-802.

[183]WuLK, YangF, XueYJ, et al., 2023. The biological functions of europium-containing biomaterials: a systematic review. Mater Today Bio, 19:100595.

[184]XieCL, ZhuangXX, NiuZM, et al., 2022. Amelioration of Alzheimer’s disease pathology by mitophagy inducers identified via machine learning and a cross-species workflow. Nat Biomed Eng, 6:76-93.

[185]XieYX, JiangJN, TangQY, et al., 2020. Iron oxide nanoparticles as autophagy intervention agents suppress hepatoma growth by enhancing tumoricidal autophagy. Adv Sci, 7(16):1903323.

[186]XuST, YangP, QianK, et al., 2022. Modulating autophagic flux via ROS-responsive targeted micelles to restore neuronal proteostasis in Alzheimer’s disease. Bioact Mater, 11:300-316.

[187]XueX, WangLR, SatoY, et al., 2014. Single-walled carbon nanotubes alleviate autophagic/lysosomal defects in primary glia from a mouse model of Alzheimer’s disease. Nano Lett, 14(9):5110-5117.

[188]YanS, ZhengX, LinYQ, et al., 2023. Cas9-mediated replacement of expanded CAG repeats in a pig model of Huntington’s disease. Nat Biom Eng, 7(5):629-646.

[189]YangL, LiP, FuSN, et al., 2010. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab, 11(6):467-478.

[190]YangZX, GeCC, LiuJJ, et al., 2015. Destruction of amyloid fibrils by graphene through penetration and extraction of peptides. Nanoscale, 7(44):18725-18737.

[191]YinY, TianBM, LiX, et al., 2022. Gold nanoparticles targeting the autophagy‍–‍lysosome system to combat the inflammation-compromised osteogenic potential of periodontal ligament stem cells: from mechanism to therapy. Biomaterials, 288:121743.

[192]ZengJL, MartinA, HanX, et al., 2019a. Biodegradable PLGA nanoparticles restore lysosomal acidity and protect neural PC-12 cells against mitochondrial toxicity. Ind Eng Chem Res, 58(31):13910-13917.

[193]ZengJL, ShirihaiOS, GrinstaffMW, 2019b. Degradable nanoparticles restore lysosomal pH and autophagic flux in lipotoxic pancreatic beta cells. Adv Healthcare Mater, 8(12):1801511.

[194]ZengJL, Acin-PerezR, AssaliEA, et al., 2023. Restoration of lysosomal acidification rescues autophagy and metabolic dysfunction in non-alcoholic fatty liver disease. Nat Commun, 14:2573.

[195]ZhangC, RenJ, HeJ, et al., 2018. Long-term monitoring of tumor-related autophagy in vivo by Fe3O4-NO· nanoparticles. Biomaterials, 179:186-198.

[196]ZhangJ, QinX, WangB, et al., 2017. Zinc oxide nanoparticles harness autophagy to induce cell death in lung epithelial cells. Cell Death Dis, 8(7):e2954.

[197]ZhangJQ, ZhuSS, JinPP, et al., 2020. Graphene oxide improves postoperative cognitive dysfunction by maximally alleviating amyloid beta burden in mice. Theranostics, 10(26):11908-11920.

[198]ZhangK, ZhuSO, LiJM, et al., 2021. Targeting autophagy using small-molecule compounds to improve potential therapy of Parkinson’s disease. Acta Pharm Sin B, 11(10):3015-3034.

[199]ZhangW, XuCC, SunJC, et al., 2022. Impairment of the autophagy‍–‍lysosomal pathway in Alzheimer’s diseases: pathogenic mechanisms and therapeutic potential. Acta Pharm Sin B, 12(3):1019-1040.

[200]ZhangXW, ZhuXX, TangDS, et al., 2023. Targeting autophagy in Alzheimer’s disease: animal models and mechanisms. Zool Res, 44(6):1132-1145.

[201]ZhangXY, MisraSK, MoitraP, et al., 2023. Use of acidic nanoparticles to rescue macrophage lysosomal dysfunction in atherosclerosis. Autophagy, 19(3):886-903.

[202]ZhangZQ, YuePF, LuTQ, et al., 2021. Role of lysosomes in physiological activities, diseases, and therapy. J Hematol Oncol, 14:79.

[203]ZhaoJL, TianZM, ZhaoSJ, et al., 2023. Insights into the effect of catalytic intratumoral lactate depletion on metabolic reprogramming and immune activation for antitumoral activity. Adv Sci, 10(4):2204808.

[204]ZhaoYG, CodognoP, ZhangH, 2021. Machinery, regulation and pathophysiological implications of autophagosome maturation. Nat Rev Mol Cell Biol, 22(11):733-750.

[205]ZhouHL, GongXQ, LinHY, et al., 2018. Gold nanoparticles impair autophagy flux through shape-dependent endocytosis and lysosomal dysfunction. J Mater Chem B, 6(48):8127-8136.

[206]ZhuL, WuGJ, YangXY, et al., 2019. Low density lipoprotein mimics insulin action on autophagy and glucose uptake in endothelial cells. Sci Rep, 9:3020.

[207]ZhuQ, SongJX, ChenJY, et al., 2023. Corynoxine B targets at HMGB1/2 to enhance autophagy for α‍-synuclein clearance in fly and rodent models of Parkinson’s disease. Acta Pharm Sin B, 13(6):2701-2714.

Open peer comments: Debate/Discuss/Question/Opinion

<1>

Please provide your name, email address and a comment





Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952783; E-mail: cjzhang@zju.edu.cn
Copyright © 2000 - 2025 Journal of Zhejiang University-SCIENCE