Apoptosis is the most prominent mode of programmed cell death and is necessary for the maintenance of tissue homeostasis. During cell apoptosis, a distinctive population of extracellular vesicles is generated, termed apoptotic vesicles (apoVs). ApoVs inherit a variety of biological molecules such as proteins, RNAs, nuclear components, lipids, and gasotransmitters from their parent cells. ApoVs have shown promising therapeutic potential for inflammation, tumors, immune disorders, and tissue regeneration. In addition, apoVs can be used as drug carriers, vaccine development, and disease diagnosis. Recently, apoVs have been used in clinical trials to treat a variety of diseases, such as temporomandibular joint osteoarthritis and the regeneration of functional alveolar bone. Here, we review the history of apoV research, current preclinical and clinical studies, and the potential issues of apoV application.
BoufenzerACarrascoKJollyLBrustolinBDi-PilloEDeriveMGibotS.2021. Potentiation of NETs release is novel characteristic of TREM-1 activation and the pharmacological inhibition of TREM-1 could prevent from the deleterious consequences of NETs release in sepsis. Cell Mol Immunol. 18(2):452–460.
2.
BrandelVSchimekVGöberSHammondTBrunnthalerLSchrottmaierWCMussbacherMSachetMLiangYYReipertS, et al. 2022. Hepatectomy-induced apoptotic extracellular vesicles stimulate neutrophils to secrete regenerative growth factors. J Hepatol. 77(6):1619–1630.
3.
CaoZLiPLiYZhangMHaoMLiWMaoXMoLYangCDingX, et al. 2023. Encapsulation of nano-bortezomib in apoptotic stem cell-derived vesicles for the treatment of multiple myeloma. Small (Weinheim an der Bergstrasse, Germany). 19(40):e2301748.
4.
ChevallierPSaiaghSDehameVGuillaumeTPeterlinPBercegeaySLe BrisYBossardCGauvritIDrenoB, et al. 2021. A phase I/II feasibility vaccine study by autologous leukemic apoptotic corpse-pulsed dendritic cells for elderly AML patients. Hum Vacci Immunother. 17(10):3511–3514.
5.
DieudeMBellCTurgeonJBeillevaireDPomerleauLYangBHamelinKQiSPalletNBelandC, et al. 2015. The 20s proteasome core, active within apoptotic exosome-like vesicles, induces autoantibody production and accelerates rejection. Sci Transl Med. 7(318):318ra200.
6.
FehrEMSpoerlSHeyderPHerrmannMBekeredjian-DingIBlankNLorenzHMSchillerM.2013. Apoptotic-cell-derived membrane vesicles induce an alternative maturation of human dendritic cells which is disturbed in SLE. J Autoimmun. 40:86–95.
7.
FranceschiniTVasuriFMuratoriPMuratoriLGuidoMLenziMD’ErricoA.2021. A practical histological approach to the diagnosis of autoimmune hepatitis: experience of an Italian tertiary referral center. Virchows Arch. 479(5):937–945.
8.
FuYHeYWuDSuiBJinYHuXShiS.2023. Apoptotic vesicles: emerging concepts and research progress in physiology and therapy. Life Med. 2(2):lnad013.
9.
GuiLYeQYuLDouGZhouYLiuYZhangYYangXJinFLiuS, et al. 2024. Bone-targeting peptide and RNF146 modified apoptotic extracellular vesicles alleviate osteoporosis. Int J Nanomed. 19:471–488.
10.
HuHZhangHBuZLiuZLvFPanMHuangXChengL.2022. Small extracellular vesicles released from bioglass/hydrogel scaffold promote vascularized bone regeneration by transferring miR-23a-3p. Int J Nanomedicine. 17:6201–6220.
11.
HuangXLanYShenJChenZXieZ.2022. Extracellular vesicles in bone homeostasis: emerging mediators of osteoimmune interactions and promising therapeutic targets. Int J Biol Sci. 18(10):4088–4100.
12.
JhanYYPrasca-ChamorroDPalou ZunigaGMooreDMArun KumarSGaharwarAKBishopCJ. 2020. Engineered extracellular vesicles with synthetic lipids via membrane fusion to establish efficient gene delivery. Int J Pharm. 573:118802.
13.
JuYHuYYangPXieXFangB.2023. Extracellular vesicle-loaded hydrogels for tissue repair and regeneration. Mater Today Bio. 18:100522.
KerrJFWyllieAHCurrieAR. 1972. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 26(4):239–257.
16.
KoopmanKRomeijnTRde LeeuwKJonkmanMFPasHHDiercksGFH. 2017. Nuclear proteins and apoptotic bodies are found in the lupus band of patients with cutaneous lupus erythematosus. J Invest Dermatol. 137(12):2652–2654.
17.
KrishnanSRBebawyM.2023. Circulating biosignatures in multiple myeloma and their role in multidrug resistance. Mol Cancer. 22(1):79.
18.
LiMXingXHuangHLiangCGaoXTangQXuXYangJLiaoLTianW.2022. BMSC-derived ApoEVs promote craniofacial bone repair via ROS/JNK signaling. J Dent Res. 101(6):714–723.
19.
LiXLiSFuXWangY.2024. Apoptotic extracellular vesicles restore homeostasis of the articular microenvironment for the treatment of rheumatoid arthritis. Bioact Mater. 35:564–576.
20.
LiZWuMLiuSLiuXHuanYYeQYangXGuoHLiuAHuangX, et al. 2022. Apoptotic vesicles activate autophagy in recipient cells to induce angiogenesis and dental pulp regeneration. Mol Ther. 30(10):3193–3208.
21.
LinRZhangTGaoJ.2023. Apoptotic vesicles of MSCs: the natural therapeutic agents and bio-vehicles for targeting drug delivery. Small (Weinheim an der Bergstrasse, Germany). 19(47):2301671.
22.
LiuDKouXChenCLiuSLiuYYuWYuTYangRWangRZhouY, et al. 2018. Circulating apoptotic bodies maintain mesenchymal stem cell homeostasis and ameliorate osteopenia via transferring multiple cellular factors. Cell Res. 28(9):918–933.
23.
LiuJQiuXLvYZhengCDongYDouGZhuBLiuAWangWZhouJ, et al. 2020. Apoptotic bodies derived from mesenchymal stem cells promote cutaneous wound healing via regulating the functions of macrophages. Stem Cell Res Ther. 11(1):507.
24.
LopezJTaitSW. 2015. Mitochondrial apoptosis: killing cancer using the enemy within. Br J Cancer. 112(6):957–962.
25.
MaLChenCLiuDHuangZLiJLiuHKin KwokRTTangBSuiBZhangX, et al. 2023. Apoptotic extracellular vesicles are metabolized regulators nurturing the skin and hair. Bioact Mater. 19:626–641.
26.
Maoet al. 2023. The Safety and Efficacy of Alveolar Bone Defect Repair Induced by Gelatin Sponge-loaded Apoptotic Vesicle Complex. Clinicaltrials.gov identifier: NCT05971342. Updated August 2, 2023. [accessed 2023 Jun 14]. https://clinicaltrials.gov/study/NCT05971342
27.
Marin-GallenSClemente-CasaresXPlanasRPujol-AutonellICarrascalJCarrilloJAmpudiaRVerdaguerJPujol-BorrellRBorràsFE, et al. 2010. Dendritic cells pulsed with antigen-specific apoptotic bodies prevent experimental type 1 diabetes. Clin Exp Immunol. 160(2):207–214.
28.
MoriMALudwigRGGarcia-MartinRBrandãoBBKahnCR. 2019. Extracellular mirnas: from biomarkers to mediators of physiology and disease. Cell Metab. 30(4):656–673.
29.
Muhsin-SharafaldineMRSaundersonSCDunnACFaedJMKleffmannTMcLellanAD. 2016. Procoagulant and immunogenic properties of melanoma exosomes, microvesicles and apoptotic vesicles. Oncotarget. 7(35):56279–56294.
30.
OuQQiaoXLiZNiuLLeiFChengRXieTYangNLiuYFuL, et al. 2024. Apoptosis releases hydrogen sulfide to inhibit Th17 cell differentiation. Cell Metab. 36(1):78–89.e75.
31.
OuQTanLShaoYLeiFHuangWYangNQuYCaoZNiuLLiuY, et al. 2022. Electrostatic charge-mediated apoptotic vesicle biodistribution attenuates sepsis by switching neutrophil netosis to apoptosis. Small (Weinheim an der Bergstrasse, Germany). 18(20):e2200306.
32.
PalmaMHanssonLChoudhuryANäsman-GlaserBErikssonIAdamsonLRossmannEWidénKHorváthRKokhaeiP, et al. 2012. Vaccination with dendritic cells loaded with tumor apoptotic bodies (Apo-Dc) in patients with chronic lymphocytic leukemia: effects of various adjuvants and definition of immune response criteria. Cancer Immunol Immunother: CII. 61(6):865–879.
33.
ParkSJKimJMKimJHurJParkSKimKShinHJChwaeYJ. 2018. Molecular mechanisms of biogenesis of apoptotic exosome-like vesicles and their roles as damage-associated molecular patterns. Proc Natl Acad Sci U S A. 115(50):E11721–E11730.
34.
PavlyukovMSYuHBastolaSMinataMShenderVOLeeYZhangSWangJKomarovaSWangJ, et al. 2018. Apoptotic cell-derived extracellular vesicles promote malignancy of glioblastoma via intercellular transfer of splicing factors. Cancer Cell. 34(1):119–135.e110.
35.
PfefferCMSinghATK. 2018. Apoptosis: a target for anticancer therapy. Int J Mol Sci. 19(2):448.
36.
RubenJMvan den AnckerWBontkesHJWestersTMHooijbergEOssenkoppeleGJde GruijlTDvan de LoosdrechtAA. 2014. Apoptotic blebs from leukemic cells as a preferred source of tumor-associated antigen for dendritic cell-based vaccines. Cancer Immunol Immunother: CII. 63(4):335–345.
37.
SamosJGarcía-OlmoDCPicazoMGRubio-VitallerAGarcía-OlmoD.2006. Circulating nucleic acids in plasma/serum and tumor progression: are apoptotic bodies involved? An experimental study in a rat cancer model. Ann N Y Acad Sci. 1075:165–173.
38.
SantavanondJPRutterSFAtkin-SmithGKPoonIKH. 2021. Apoptotic bodies: mechanism of formation, isolation and functional relevance. In: MathivananSFonsekaPNedevaC, et al., editors. New frontiers: extracellular vesicles. Cham (UK): Springer International. p. 61–88.
39.
ShaoYJiangYYangKZhuYLiuYZhangPLvLZhangXZhouY.2023. Apoptotic vesicles derived from human red blood cells promote bone regeneration via carbonic anhydrase 1. Cell Prolif. 57(2):e13547.
40.
SuiBWangRChenCKouXWuDFuYLeiFWangYLiuYChenX, et al. 2024. Apoptotic vesicular metabolism contributes to organelle assembly and safeguards liver homeostasis and regeneration. Gastroenterology. 167(2):343–356.
41.
ViswanathanVJuluriRGoelSMadanJMitraSKGopalakrishnanD.2015. Apoptotic index and proliferative index in premalignant and malignant squamous cell lesions of the oral cavity. J Int Oral Health. 7(1):40–43.
WangRHaoMKouXSuiBSanmillanMLZhangXLiuDTianJYuWChenC, et al. 2023. Apoptotic vesicles ameliorate lupus and arthritis via phosphatidylserine-mediated modulation of T cell receptor signaling. Bioact Mater. 25:472–484.
44.
WangYPangJWangQYanLWangLXingZWangCZhangJDongL.2021. Delivering antisense oligonucleotides across the blood-brain barrier by tumor cell-derived small apoptotic bodies. Adv Sci. 8(13):2004929.
45.
WinauFWeberSSadSde DiegoJHoopsSLBreidenBSandhoffKBrinkmannVKaufmannSHSchaibleUE. 2006. Apoptotic vesicles crossprime CD8 T cells and protect against tuberculosis. Immunity. 24(1):105–117.
46.
WorbsTHammerschmidtSIFörsterR.2017. Dendritic cell migration in health and disease. Nat Rev Immunol. 17(1):30–48.
47.
WuPZhangBOcanseyDKWXuWQianH.2021. Extracellular vesicles: a bright star of nanomedicine. Biomater. 269:120467.
48.
XuXLaiYHuaZ-C.2019. Apoptosis and apoptotic body: disease message and therapeutic target potentials. Biosci Rep. 39(1):BSR20180992.
49.
XuanKLiBGuoHSunWKouXHeXZhangYSunJLiuALiaoL, et al. 2018. Deciduous autologous tooth stem cells regenerate dental pulp after implantation into injured teeth. Sci Transl Med. 10(455): eaaf3227.
50.
YeQXuHLiuSLiZZhouJDingFZhangXWangYJinYWangQ.2022. Apoptotic extracellular vesicles alleviate Pg-LPS induced inflammatory responses of macrophages via AMPK/SIRT1/NF-κB pathway and inhibit osteoclast formation. J Periodontol. 93(11):1738–1751.
51.
YongTZhangXBieNZhangHZhangXLiFHakeemAHuJGanLSantosHA, et al. 2019. Tumor exosome-based nanoparticles are efficient drug carriers for chemotherapy. Nat Commun. 10(1):3838.
52.
YuLZhuGZhangZYuYZengLXuZWengJXiaJLiJPathakJL. 2023. Apoptotic bodies: bioactive treasure left behind by the dying cells with robust diagnostic and therapeutic application potentials. J Nanobiotechnology. 21(1):218.
53.
ZhangGHuangXXiuHSunYChenJChengGSongZPengYShenYWangJ, et al. 2020. Extracellular vesicles: natural liver-accumulating drug delivery vehicles for the treatment of liver diseases. J Extracell Vesicles. 10(2):e12030.
54.
ZhangSYangYJiaSChenHDuanYLiXWangSWangTLyuYChenG, et al. 2020. Exosome-like vesicles derived from hertwig’s epithelial root sheath cells promote the regeneration of dentin-pulp tissue. Theranostics. 10(13):5914–5931.
55.
ZhangXTangJKouXHuangWZhuYJiangYYangKLiCHaoMQuY, et al. 2022. Proteomic analysis of MSC-derived apoptotic vesicles identifies Fas inheritance to ameliorate haemophilia a via activating platelet functions. J Extracell Vesicles. 11(7):e12240.
56.
ZhengCSuiBZhangXHuJChenJLiuJWuDYeQXiangLQiuX, et al. 2021. Apoptotic vesicles restore liver macrophage homeostasis to counteract type 2 diabetes. J Extracell Vesicles. 10(7):e12109.
57.
ZhongWQRenJGXiongXPManQWZhangWGaoLLiCLiuBSunZJJiaJ, et al. 2019. Increased salivary microvesicles are associated with the prognosis of patients with oral squamous cell carcinoma. J Cell Mol Med. 23(6):4054–4062.
58.
ZhouMLiY-JTangY-CHaoX-YXuW-JXiangD-XWuJ-Y.2022. Apoptotic bodies for advanced drug delivery and therapy. J Control Release. 351:394–406.
59.
ZhuYYangKChengYLiuYGuRLiuXLiuHZhangXLiuY.2023. Apoptotic vesicles regulate bone metabolism via the miR1324/SNX14/SMAD1/5 signaling axis. Small (Weinheim an der Bergstrasse, Germany). 19(16):e2205813.
60.
ZouXLeiQLuoXYinJChenSHaoCShiyuLMaD.2023. Advances in biological functions and applications of apoptotic vesicles. Cell Commun Signal. 21(1):260.
