{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T23:54:38Z","timestamp":1791417278489,"version":"4.3.3"},"reference-count":71,"publisher":"Wiley","issue":"15","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Cellular Molecular Medi"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Proteolysis\u2010targeting chimeras (PROTACs) are heterobifunctional molecules that hijack the ubiquitin\u2010proteasome system to drive catalytic, sub\u2010stoichiometric degradation of disease\u2010associated proteins, offering a mechanistic advantage over occupancy\u2010driven inhibitors and access to \u2018undruggable\u2019 targets. However, their clinical translation is constrained by high molecular weight, poor solubility, low oral bioavailability, inefficient membrane permeability, nonspecific biodistribution, off\u2010target degradation, and the concentration\u2010dependent \u2018hook effect.\u2019 Exosomes, nanoscale extracellular vesicles with innate biocompatibility, low immunogenicity, prolonged circulation, and the ability to cross barriers such as the blood\u2013brain barrier, offer a biologically integrated platform to overcome these limitations. This review traces the evolution of PROTAC technology, delineates the challenges of conventional delivery, and evaluates the rationale for exosomal encapsulation, including cargo protection, intracellular trafficking, endosomal escape, and release kinetics. We examine natural and engineered exosomes spanning source selection, active loading strategies, and surface functionalization for tissue\u2010specific homing and synthesize therapeutic applications across viral infections, cancer, neurodegenerative disorders, and inflammatory diseases. Proof\u2010of\u2010concept studies, such as camel milk\u2010derived exosomes delivering the BRD4\u2010targeting PROTAC ARV\u2010825, demonstrate enhanced permeability, lower IC\n                    <jats:sub>50<\/jats:sub>\n                    values, and improved oral bioavailability. Finally, we discuss key hurdles to clinical translation: scalable production, purification, and standardization, and outline future directions for exosome\u2010mediated targeted protein degradation.\n                  <\/jats:p>","DOI":"10.1111\/jcmm.71297","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T04:44:31Z","timestamp":1785386671000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Exosome\u2010Mediated Delivery of\n                    <scp>PROTACs<\/scp>\n                    for Targeted Protein Degradation in Cancer, Neurodegenerative, Infectious, and Inflammatory Diseases"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2768-0950","authenticated-orcid":false,"given":"Sruti Bagchi","family":"Ghosh","sequence":"first","affiliation":[{"name":"Department of Pharmacy Calcutta Institute of Pharmaceutical Technology and Allied Health Sciences  Howrah West Bengal India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6463-4155","authenticated-orcid":false,"given":"Rumpa","family":"Banerjee","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Eminent College of Pharmaceutical Technology  Barasat West Bengal India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hailah M.","family":"Almohaimeed","sequence":"additional","affiliation":[{"name":"Department of Basic Science, College of Medicine Princess Nourah Bint Abdulrahman University  Riyadh Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5302-6309","authenticated-orcid":false,"given":"Amany I.","family":"Almars","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences King Abdulaziz University  Jeddah Saudi Arabia"},{"name":"Hematology Research Unit, King Fahd Medical Research Center King Abdulaziz University  Jeddah Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8098-2398","authenticated-orcid":false,"given":"Tahani Ahmad","family":"ALMatrafi","sequence":"additional","affiliation":[{"name":"Department of Anatomy, College of Medicine King Saud University  Riyadh Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fayez M.","family":"Saleh","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Faculty of Medicine University of Tabuk  Tabuk Saudi Arabia"},{"name":"Molecular Microbiology and Infectious Diseases Research Unit University of Tabuk  Tabuk Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7391-0529","authenticated-orcid":false,"given":"Zuhair M.","family":"Mohammedsaleh","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences University of Tabuk  Tabuk Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2985-538X","authenticated-orcid":false,"given":"Kranti Kiran Reddy","family":"Ealla","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Pathology Malla Reddy Institute of Dental Sciences, Malla Reddy Vishwavidyapeeth  Hyderabad Telangana India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5136-6166","authenticated-orcid":false,"given":"Ajoy","family":"Kumer","sequence":"additional","affiliation":[{"name":"Department of Chemistry IUBAT\u2010International University of Business Agriculture &amp; Technology  Dhaka Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5433-1994","authenticated-orcid":false,"given":"Bikram","family":"Dhara","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Saveetha Medical College and Hospital Saveetha Institute of Medical and Technical Sciences  Chennai Tamil Nadu India"},{"name":"Department of Translational Medicine and Extracellular Vesicle Research ExoVesicle Biosciences  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-010715-103507"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/vetsci10020124"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cclet.2025.112338"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules28104014"},{"key":"e_1_2_12_6_1","first-page":"1","article-title":"Options to Improve the Action of PROTACs in Cancer: Development of Controlled Delivery Nanoparticles","volume":"10","author":"Juan A.","year":"2022","journal-title":"Frontiers in Cell and Developmental Biology"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2017.125"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aau6977"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.52570"},{"key":"e_1_2_12_10_1","article-title":"PROTAC\u2010Based Therapeutics for Targeting HPV Oncoproteins in Head and Neck Cancers","volume":"4","author":"Mukerjee N.","year":"2025","journal-title":"Nanomedicine and Translational Medicine"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mtbio.2025.101613"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics16081070"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2022.1009338"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12951-018-0388-4"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/ctd2.328"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells12141846"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gpb.2015.02.001"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.29926"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cej.2025.160915"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21186466"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jddst.2024.106596"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2024.104044"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12951\u2010018\u201004039"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22031144"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2022.105480"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajps.2023.100797"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2015.10.020"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsnano.2c04337"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22031115"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2023.1100310"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ntm.2025.100071"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsanm.3c04537"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/ctd2.337"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.4155\/fmc-2018-0417"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12951\u2010019\u20100526\u20107"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.3390\/curroncol29020055"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12916\u2010018\u20101163\u2010y"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.743189"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2021.13080"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471\u20102407\u201014\u2010176"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2020.00564"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2021.136414"},{"key":"e_1_2_12_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-67460-1"},{"key":"e_1_2_12_44_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.62069"},{"key":"e_1_2_12_45_1","article-title":"Mesenchymal Stem Cell\u2010Derived Exosomes Ameliorate Alzheimer's Disease Pathology and Improve Cognitive Deficits","volume":"9","author":"Chen Y. 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