Engineered extracellular vesicles: A new approach for targeted therapy of tumors and overcoming drug resistance

Ming-Kun Chen, Zi-Xian Chen, Mao-Ping Cai, Hong Chen, Zhuang-Fei Chen, Shan-Chao Zhao

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Cancer Communications ›› 2024, Vol. 44 ›› Issue (2) : 205-225. DOI: 10.1002/cac2.12518
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Engineered extracellular vesicles: A new approach for targeted therapy of tumors and overcoming drug resistance

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Abstract

Targeted delivery of anti-tumor drugs and overcoming drug resistance in malignant tumor cells remain significant clinical challenges. However, there are only few effective methods to address these issues. Extracellular vesicles (EVs), actively secreted by cells, play a crucial role in intercellular information transmission and cargo transportation. Recent studies have demonstrated that engineered EVs can serve as drug delivery carriers and showed promising application prospects. Nevertheless, there is an urgent need for further improvements in the isolation and purification of EVs, surface modification techniques, drug assembly processes, and precise recognition of tumor cells for targeted drug delivery purposes. In this review, we summarize the applications of engineered EVs in cancer treatment and overcoming drug resistance, and current challenges associated with engineered EVs are also discussed. This review aims to provide new insights and potential directions for utilizing engineered EVs as targeted delivery systems for anti-tumor drugs and overcoming drug resistance in the near future.

Keywords

drug delivery / drug resistance / extracellular vesicles / nanoparticles

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Ming-Kun Chen, Zi-Xian Chen, Mao-Ping Cai, Hong Chen, Zhuang-Fei Chen, Shan-Chao Zhao. Engineered extracellular vesicles: A new approach for targeted therapy of tumors and overcoming drug resistance. Cancer Communications, 2024, 44(2): 205‒225 https://doi.org/10.1002/cac2.12518

References

[1]
MillerKD, Nogueira L, DevasiaT, MariottoAB, Yabroff KR, JemalA, et al. Cancer treatment and survivorship statistics, 2022. CA Cancer J Clin. 2022;72(5):409–436.
[2]
ChenE, Abu-Sbeih H, ThirumurthiS, MallepallyN, Khurana S, WeiD, et al. Clinical characteristics of colitis induced by taxane-based chemotherapy. Ann Gastroenterol. 2020;33(1):59–67.
[3]
PalukuriNR, YedlaRP, BalaSC, Kuruva SP, ChennamaneniR, KonatamML, et al. Incidence of febrile neutropenia with commonly used chemotherapy regimen in localized breast cancer. South Asian J Cancer. 2020;9(1):4–6.
[4]
LiuD, YangF, XiongF, Gu N. The smart drug delivery system and its clinical potential. Theranostics. 2016;6(9):1306–1323.
[5]
MatsumuraY. The drug discovery by nanomedicine and its clinical experience. Jpn J Clin Oncol. 2014;44(6):515–525.
[6]
HaqueS, Whittaker MR, McIntoshMP, PoutonCW, Kaminskas LM. Disposition and safety of inhaled biodegradable nanomedicines: Opportunities and challenges. Nanomedicine. 2016;12(6):1703–1724.
[7]
VaderP, MolEA, PasterkampG, Schiffelers RM. Extracellular vesicles for drug delivery. Adv Drug Deliv Rev. 2016;106(Pt A):148–156.
[8]
BatrakovaEV, KimMS. Using exosomes, naturally-equipped nanocarriers, for drug delivery. J Control Release. 2015;219:396–405.
[9]
BangC, ThumT. Exosomes: New players in cell-cell communication. Int J Biochem Cell Biol. 2012;44(11):2060–2064.
[10]
MorseMA, GarstJ, OsadaT, Khan S, HobeikaA, ClayTM, et al. A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer. J Transl Med. 2005;3(1):9.
[11]
DaiS, WeiD, WuZ, ZhouX, WeiX, HuangH, et al. Phase I clinical trial of autologous ascites-derived exosomes combined with GM-CSF for colorectal cancer. Mol Ther. 2008;16(4):782–790.
[12]
MorishitaM, Takahashi Y, MatsumotoA, NishikawaM, Takakura Y. Exosome-based tumor antigens-adjuvant co-delivery utilizing genetically engineered tumor cell-derived exosomes with immunostimulatory CpG DNA. Biomaterials. 2016;111:55–65.
[13]
UrbanelliL, Buratta S, SaginiK, FerraraG, LanniM, EmilianiC. Exosome-based strategies for Diagnosis and Therapy. Recent Pat CNS Drug Discov. 2015;10(1):10–27.
[14]
KouL, BhutiaYD, YaoQ, HeZ, SunJ, Ganapathy V. Transporter-Guided delivery of nanoparticles to improve drug permeation across cellular barriers and drug exposure to selective cell types. Front Pharmacol. 2018;9:27.
[15]
BlancoE, ShenH, FerrariM. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat Biotechnol. 2015;33(9):941–951.
[16]
NgouneR, PetersA, von ElverfeldtD, WinklerK, Pütz G. Accumulating nanoparticles by EPR: A route of no return. J Control Release. 2016;238:58–70.
[17]
AnselmoAC, Mitragotri S. Nanoparticles in the clinic. Bioeng Transl Med. 2016;1(1):10–29.
[18]
ChenG, WangY, XieR, GongS. Tumor-targeted pH/redox dual-sensitive unimolecular nanoparticles for efficient siRNA delivery. J Control Release. 2017;259:105–114.
[19]
MohammadF, Al-Lohedan HA. Luteinizing hormone-releasing hormone targeted superparamagnetic gold nanoshells for a combination therapy of hyperthermia and controlled drug delivery. Mater Sci Eng C Mater Biol Appl. 2017;76:692–700.
[20]
QiaoY, WanJ, ZhouL, Ma W, YangY, LuoW, et al. Stimuli-responsive nanotherapeutics for precision drug delivery and cancer therapy. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2019;11(1):e1527.
[21]
LvT, YuT, FangY, Zhang S, JiangM, ZhangH, et al. Role of generation on folic acid-modified poly(amidoamine) dendrimers for targeted delivery of baicalin to cancer cells. Mater Sci Eng C Mater Biol Appl. 2017;75:182–190.
[22]
XuL, Yeudall WA, YangH. Folic acid-decorated polyamidoamine dendrimer exhibits high tumor uptake and sustained highly localized retention in solid tumors: Its utility for local siRNA delivery. Acta Biomater. 2017;57:251–261.
[23]
MuralidharanR, BabuA, AmreddyN, Basalingappa K, MehtaM, ChenA, et al. Folate receptor-targeted nanoparticle delivery of HuR-RNAi suppresses lung cancer cell proliferation and migration. J Nanobiotechnology. 2016;14(1):47.
[24]
DanielsTR, Bernabeu E, RodríguezJA, PatelS, KozmanM, ChiappettaDA, et al. The transferrin receptor and the targeted delivery of therapeutic agents against cancer. Biochim Biophys Acta. 2012;1820(3):291–317.
[25]
LiuL, WeiY, ZhaiS, Chen Q, XingD. Dihydroartemisinin and transferrin dual-dressed nano-graphene oxide for a pH-triggered chemotherapy. Biomaterials. 2015;62:35–46.
[26]
PantK, NeuberC, ZarschlerK, Wodtke J, MeisterS, HaagR, et al. Active targeting of dendritic polyglycerols for diagnostic cancer imaging. Small. 2020;16(7):e1905013.
[27]
NasrollahiF, KohYR, ChenP, Varshosaz J, KhodadadiAA, LimS. Targeting graphene quantum dots to epidermal growth factor receptor for delivery of cisplatin and cellular imaging. Mater Sci Eng C Mater Biol Appl. 2019;94:247–257.
[28]
AgnelloL, Tortorella S, d'ArgenioA, CarboneC, Camorani S, LocatelliE, et al. Optimizing cisplatin delivery to triple-negative breast cancer through novel EGFR aptamer-conjugated polymeric nanovectors. J Exp Clin Cancer Res. 2021;40(1):239.
[29]
FuZ, XiangJ. Aptamers, the nucleic acid antibodies, in cancer therapy. Int J Mol Sci. 2020;21(8):2793.
[30]
FarokhzadOC, ChengJ, TeplyBA, Sherifi I, JonS, KantoffPW, et al. Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo. Proc Natl Acad Sci U S A. 2006;103(16):6315–6320.
[31]
WuX, DingB, GaoJ, WangH, FanW, WangX, et al. Second-generation aptamer-conjugated PSMA-targeted delivery system for prostate cancer therapy. Int J Nanomedicine. 2011;6:1747–1756.
[32]
WuL, LiuF, YinL, WangF, ShiH, ZhaoQ, et al. The establishment of polypeptide PSMA-targeted chimeric antigen receptor-engineered natural killer cells for castration-resistant prostate cancer and the induction of ferroptosis-related cell death. Cancer Commun (Lond). 2022;42(8):768–783.
[33]
TassevDV, ChengM, CheungNK. Retargeting NK92 cells using an HLA-A2-restricted, EBNA3C-specific chimeric antigen receptor. Cancer Gene Ther. 2012;19(2):84–100.
[34]
MitragotriS, Lammers T, BaeYH, SchwendemanS, De Smedt S, LerouxJC, et al. Drug delivery research for the future: Expanding the nano horizons and beyond. J Control Release. 2017;246:183–184.
[35]
ZolnikBS, González-Fernández A, SadriehN, DobrovolskaiaMA. Nanoparticles and the immune system. Endocrinology. 2010;151(2):458–465.
[36]
LiuY, HardieJ, ZhangX, Rotello VM. Effects of engineered nanoparticles on the innate immune system. Semin Immunol. 2017;34:25–32.
[37]
SzebeniJ, StormG. Complement activation as a bioequivalence issue relevant to the development of generic liposomes and other nanoparticulate drugs. Biochem Biophys Res Commun. 2015;468(3):490–497.
[38]
SzebeniJ, Moghimi SM. Liposome triggering of innate immune responses: A perspective on benefits and adverse reactions. J Liposome Res. 2009;19(2):85–90.
[39]
LavermanP, Carstens MG, BoermanOC, DamsET, OyenWJ, van RooijenN, et al. Factors affecting the accelerated blood clearance of polyethylene glycol-liposomes upon repeated injection. J Pharmacol Exp Ther. 2001;298(2):607–612.
[40]
SchellekensH, Hennink WE, BrinksV. The immunogenicity of polyethylene glycol: Facts and fiction. Pharmaceutical Research. 2013;30(7):1729–1734.
[41]
GabizonAA. Stealth liposomes and tumor targeting: One step further in the quest for the magic bullet. Clin Cancer Res. 2001;7(2):223–225.
[42]
TinkleS, McNeilSE, MühlebachS, BawaR, Borchard G, BarenholzYC, et al. Nanomedicines: Addressing the scientific and regulatory gap. Ann N Y Acad Sci. 2014;1313:35–56.
[43]
GraingerDW. Connecting drug delivery reality to smart materials design. Int J Pharm. 2013;454(1):521–524.
[44]
NyströmAM, FadeelB. Safety assessment of nanomaterials: Implications for nanomedicine. J Control Release. 2012;161(2):403–408.
[45]
van der PolE, Böing AN, HarrisonP, SturkA, Nieuwland R. Classification, functions, and clinical relevance of extracellular vesicles. Pharmacol Rev. 2012;64(3):676–705.
[46]
EversMJW, van de Wakker SI, de GrootEM, de JongOG, Gitz-François JJJ, SeinenCS, et al. Functional siRNA delivery by extracellular vesicle-liposome hybrid nanoparticles. Adv Healthc Mater. 2022;11(5):e2101202.
[47]
RoerigJ, Mitrach F, SchmidM, HauseG, HackerMC, WölkC, et al. Synergistic siRNA loading of extracellular vesicles enables functional delivery into cells. Small Methods. 2022;6(12):e2201001.
[48]
PanBT, Johnstone RM. Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: Selective externalization of the receptor. Cell. 1983;33(3):967–978.
[49]
JiaS, ZoccoD, SamuelsML, Chou MF, ChammasR, SkogJ, et al. Emerging technologies in extracellular vesicle-based molecular diagnostics. Expert Rev Mol Diagn. 2014;14(3):307–321.
[50]
VlassovAV, Magdaleno S, SetterquistR, ConradR. Exosomes: Current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials. Biochim Biophys Acta. 2012;1820(7):940–948.
[51]
SahooS, Klychko E, ThorneT, MisenerS, Schultz KM, MillayM, et al. Exosomes from human CD34(+) stem cells mediate their proangiogenic paracrine activity. Circ Res. 2011;109(7):724–728.
[52]
KalluriR, LeBleuVS. The biology, function, and biomedical applications of exosomes. Science. 2020;367(6478):eaau6977.
[53]
LässerC, Alikhani VS, EkströmK, EldhM, Paredes PT, BossiosA, et al. Human saliva, plasma and breast milk exosomes contain RNA: Uptake by macrophages. J Transl Med. 2011;9:9.
[54]
PisitkunT, ShenRF, KnepperMA. Identification and proteomic profiling of exosomes in human urine. Proc Natl Acad Sci U S A. 2004;101(36):13368–13373.
[55]
van DommelenSM, VaderP, LakhalS, Kooijmans SA, van SolingeWW, WoodMJ, et al. Microvesicles and exosomes: Opportunities for cell-derived membrane vesicles in drug delivery. J Control Release. 2012;161(2):635–644.
[56]
SmythT, Kullberg M, MalikN, Smith-JonesP, GranerMW, AnchordoquyTJ. Biodistribution and delivery efficiency of unmodified tumor-derived exosomes. J Control Release. 2015;199:145–155.
[57]
HeC, ZhengS, LuoY, WangB. Exosome theranostics: Biology and translational medicine. Theranostics. 2018;8(1):237–255.
[58]
Rufino-RamosD, Albuquerque PR, CarmonaV, PerfeitoR, NobreRJ, Pereira de AlmeidaL. Extracellular vesicles: Novel promising delivery systems for therapy of brain diseases. J Control Release. 2017;262:247–258.
[59]
TianT, ZhangHX, HeCP, FanS, ZhuYL, Qi C, et al. Surface functionalized exosomes as targeted drug delivery vehicles for cerebral ischemia therapy. Biomaterials. 2018;150:137–149.
[60]
ShaoH, ChungJ, BalajL, Charest A, BignerDD, CarterBS, et al. Protein typing of circulating microvesicles allows real-time monitoring of glioblastoma therapy. Nat Med. 2012;18(12):1835–1840.
[61]
ThéryC, WitwerKW, AikawaE, Alcaraz MJ, AndersonJD, AndriantsitohainaR, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): A position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles. 2018;7(1):1535750.
[62]
WanT, ZhongJ, PanQ, ZhouT, PingY, Liu X. Exosome-mediated delivery of Cas9 ribonucleoprotein complexes for tissue-specific gene therapy of liver diseases. Sci Adv. 2022;8(37):eabp9435.
[63]
JeppesenDK, FenixAM, FranklinJL, Higginbotham JN, ZhangQ, ZimmermanLJ, et al. Reassessment of exosome composition. Cell. 2019;177(2):428–445. e18.
[64]
WuY, DengW, KlinkeDJ. Exosomes: Improved methods to characterize their morphology, RNA content, and surface protein biomarkers. Analyst. 2015;140(19):6631–6642.
[65]
PospichalovaV, Svoboda J, DaveZ, KotrbovaA, KaiserK, KlemovaD, et al. Simplified protocol for flow cytometry analysis of fluorescently labeled exosomes and microvesicles using dedicated flow cytometer. J Extracell Vesicles. 2015;4:25530.
[66]
IslamMK, SyedP, LehtinenL, Leivo J, GidwaniK, WittfoothS, et al. A nanoparticle-based approach for the detection of extracellular vesicles. Sci Rep. 2019;9(1):10038.
[67]
LivshitsMA, Khomyakova E, EvtushenkoEG, LazarevVN, Kulemin NA, SeminaSE, et al. Isolation of exosomes by differential centrifugation: Theoretical analysis of a commonly used protocol. Sci Rep. 2015;5:17319.
[68]
ColaoIL, Corteling R, BracewellD, WallI. Manufacturing exosomes: A promising therapeutic platform. Trends Mol Med. 2018;24(3):242–256.
[69]
YangXX, SunC, WangL, Guo XL. New insight into isolation, identification techniques and medical applications of exosomes. J Control Release. 2019;308:119–129.
[70]
VergauwenG, DhondtB, Van DeunJ, De Smedt E, BerxG, TimmermanE, et al. Confounding factors of ultrafiltration and protein analysis in extracellular vesicle research. Sci Rep. 2017;7(1):2704.
[71]
GurunathanS, KangMH, JeyarajM, Qasim M, KimJH. Review of the isolation, characterization, biological function, and multifarious therapeutic approaches of exosomes. Cells. 2019;8(4):307.
[72]
ZhangY, BiJ, HuangJ, Tang Y, DuS, LiP. Exosome: A review of its classification, isolation techniques, storage, diagnostic and targeted therapy applications. Int J Nanomedicine. 2020;15:6917–6934.
[73]
YangD, ZhangW, ZhangH, Zhang F, ChenL, MaL, et al. Progress, opportunity, and perspective on exosome isolation—efforts for efficient exosome-based theranostics. Theranostics. 2020;10(8):3684–3707.
[74]
FitzgeraldJ, Leonard P, DarcyE, SharmaS, O'Kennedy R. Immunoaffinity chromatography: Concepts and applications. Methods Mol Biol. 2017;1485:27–51.
[75]
LiP, KaslanM, LeeSH, Yao J, GaoZ. Progress in exosome isolation techniques. Theranostics. 2017;7(3):789–804.
[76]
BenedikterBJ, Bouwman FG, VajenT, HeinzmannACA, GraulsG, MarimanEC, et al. Ultrafiltration combined with size exclusion chromatography efficiently isolates extracellular vesicles from cell culture media for compositional and functional studies. Sci Rep. 2017;7(1):15297.
[77]
ShuS, AllenCL, Benjamin-DavalosS, KorolevaM, MacFarland D, MindermanH, et al. A rapid exosome isolation using ultrafiltration and size exclusion chromatography (REIUS) method for exosome isolation from melanoma cell lines. Methods Mol Biol. 2021;2265:289–304.
[78]
GuanS, YuH, YanG, GaoM, SunW, ZhangX. Characterization of urinary exosomes purified with size exclusion chromatography and ultracentrifugation. J Proteome Res. 2020;19(6):2217–2225.
[79]
MittelbrunnM, Sánchez-Madrid F. Intercellular communication: Diverse structures for exchange of genetic information. Nat Rev Mol Cell Biol. 2012;13(5):328–335.
[80]
PradaI, Meldolesi J. Binding and fusion of extracellular vesicles to the plasma membrane of their cell targets. Int J Mol Sci. 2016;17(8):1296.
[81]
TianT, WangY, WangH, Zhu Z, XiaoZ. Visualizing of the cellular uptake and intracellular trafficking of exosomes by live-cell microscopy. J Cell Biochem. 2010;111(2):488–496.
[82]
LiuQ, Rojas-Canales DM, DivitoSJ, ShufeskyWJ, StolzDB, ErdosG, et al. Donor dendritic cell-derived exosomes promote allograft-targeting immune response. J Clin Invest. 2016;126(8):2805–2820.
[83]
ColemanBM, HillAF. Extracellular vesicles–Their role in the packaging and spread of misfolded proteins associated with neurodegenerative diseases. Semin Cell Dev Biol. 2015;40:89–96.
[84]
RajendranL, BaliJ, BarrMM, Court FA, Krämer-AlbersEM, PicouF, et al. Emerging roles of extracellular vesicles in the nervous system. J Neurosci. 2014;34(46):15482–15489.
[85]
LimoniSK, Moghadam MF, MoazzeniSM, GomariH, SalimiF. Engineered exosomes for targeted transfer of siRNA to HER2 positive breast cancer cells. Appl Biochem Biotechnol. 2019;187(1):352–364.
[86]
BarileL, Vassalli G. Exosomes: Therapy delivery tools and biomarkers of diseases. Pharmacol Ther. 2017;174:63–78.
[87]
ZouJ, ShiM, LiuX, JinC, XingX, Qiu L, et al. Aptamer-Functionalized exosomes: Elucidating the cellular uptake mechanism and the potential for cancer-targeted chemotherapy. Anal Chem. 2019;91(3):2425–2430.
[88]
SmythT, Petrova K, PaytonNM, PersaudI, RedzicJS, GranerMW, et al. Surface functionalization of exosomes using click chemistry. Bioconjug Chem. 2014;25(10):1777–1784.
[89]
JiaG, HanY, AnY, DingY, HeC, WangX, et al. NRP-1 targeted and cargo-loaded exosomes facilitate simultaneous imaging and therapy of glioma in vitro and in vivo. Biomaterials. 2018;178:302–316.
[90]
AbumiyaT, LuceroJ, HeoJH, Tagaya M, KoziolJA, CopelandBR, et al. Activated microvessels express vascular endothelial growth factor and integrin alpha(v)beta3 during focal cerebral ischemia. J Cereb Blood Flow Metab. 1999;19(9):1038–1050.
[91]
HaubnerR, WesterHJ, BurkhartF, Senekowitsch-Schmidtke R, WeberW, GoodmanSL, et al. Glycosylated RGD-containing peptides: Tracer for tumor targeting and angiogenesis imaging with improved biokinetics. J Nucl Med. 2001;42(2):326–336.
[92]
ElwardK, GasqueP. “Eat me” and “don't eat me” signals govern the innate immune response and tissue repair in the CNS: Emphasis on the critical role of the complement system. Mol Immunol. 2003;40(2-4):85–94.
[93]
ChaoMP, Weissman IL, MajetiR. The CD47-SIRPα pathway in cancer immune evasion and potential therapeutic implications. Curr Opin Immunol. 2012;24(2):225–232.
[94]
NieW, WuG, ZhangJ, Huang LL, DingJ, JiangA, et al. Responsive exosome nano-bioconjugates for synergistic cancer therapy. Angew Chem Int Ed Engl. 2020;59(5):2018–2022.
[95]
JiC, WeiJ, ZhangL, Hou X, TanJ, YuanQ, et al. Aptamer-Protein interactions: From regulation to biomolecular detection. Chem Rev. 2023;123(22):12471–12506.
[96]
ShangguanD, LiY, TangZ, Cao ZC, ChenHW, MallikaratchyP, et al. Aptamers evolved from live cells as effective molecular probes for cancer study. Proc Natl Acad Sci U S A. 2006;103(32):11838–11843.
[97]
FangX, TanW. Aptamers generated from cell-SELEX for molecular medicine: A chemical biology approach. Acc Chem Res. 2010;43(1):48–57.
[98]
WangY, ChenX, TianB, Liu J, YangL, ZengL, et al. Nucleolin-targeted extracellular vesicles as a versatile platform for biologics delivery to breast cancer. Theranostics. 2017;7(5):1360–1372.
[99]
PiF, BinzelDW, LeeTJ, Li Z, SunM, RychahouP, et al. Nanoparticle orientation to control RNA loading and ligand display on extracellular vesicles for cancer regression. Nat Nanotechnol. 2018;13(1):82–89.
[100]
QiH, LiuC, LongL, Ren Y, ZhangS, ChangX, et al. Blood exosomes endowed with magnetic and targeting properties for cancer therapy. ACS Nano. 2016;10(3):3323–3333.
[101]
NakaseI, FutakiS. Combined treatment with a pH-sensitive fusogenic peptide and cationic lipids achieves enhanced cytosolic delivery of exosomes. Sci Rep. 2015;5:10112.
[102]
KooijmansSA, AlezaCG, RofflerSR, van Solinge WW, VaderP, SchiffelersRM. Display of GPI-anchored anti-EGFR nanobodies on extracellular vesicles promotes tumour cell targeting. J Extracell Vesicles. 2016;5:31053.
[103]
AkbariA, Nazari-Khanamiri F, AhmadiM, ShoaranM, RezaieJ. Engineered exosomes for tumor-targeted drug delivery: A focus on genetic and chemical functionalization. Pharmaceutics. 2022;15(1):66.
[104]
LuanX, Sansanaphongpricha K, MyersI, ChenH, YuanH, SunD. Engineering exosomes as refined biological nanoplatforms for drug delivery. Acta Pharmacol Sin. 2017;38(6):754–763.
[105]
SalunkheS, Dheeraj BM, ChitkaraD, MittalA. Surface functionalization of exosomes for target-specific delivery and in vivo imaging & tracking: Strategies and significance. J Control Release. 2020;326:599–614.
[106]
ThéryC, Zitvogel L, AmigorenaS. Exosomes: Composition, biogenesis and function. Nat Rev Immunol. 2002;2(8):569–579.
[107]
KumarP, WuH, McBrideJL, Jung KE, KimMH, DavidsonBL, et al. Transvascular delivery of small interfering RNA to the central nervous system. Nature. 2007;448(7149):39–43.
[108]
Alvarez-ErvitiL, SeowY, YinH, BettsC, LakhalS, Wood MJ. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol. 2011;29(4):341–345.
[109]
WilsonHL, NiK, O'NeillHC. Identification of progenitor cells in long-term spleen stromal cultures that produce immature dendritic cells. Proc Natl Acad Sci U S A. 2000;97(9):4784–4789.
[110]
QuahBJ, O'Neill HC. The immunogenicity of dendritic cell-derived exosomes. Blood Cells Mol Dis. 2005;35(2):94–110.
[111]
TianY, LiS, SongJ, Ji T, ZhuM, AndersonGJ, et al. A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy. Biomaterials. 2014;35(7):2383–2390.
[112]
BaiJ, DuanJ, LiuR, DuY, LuoQ, CuiY, et al. Engineered targeting tLyp-1 exosomes as gene therapy vectors for efficient delivery of siRNA into lung cancer cells. Asian J Pharm Sci. 2020;15(4):461–471.
[113]
TeesaluT, Sugahara KN, KotamrajuVR, RuoslahtiE. C-end rule peptides mediate neuropilin-1-dependent cell, vascular, and tissue penetration. Proc Natl Acad Sci U S A. 2009;106(38):16157–16162.
[114]
KawakamiT, Tokunaga T, HatanakaH, KijimaH, Yamazaki H, AbeY, et al. Neuropilin 1 and neuropilin 2 co-expression is significantly correlated with increased vascularity and poor prognosis in nonsmall cell lung carcinoma. Cancer. 2002;95(10):2196–2201.
[115]
HungME, Leonard JN. Stabilization of exosome-targeting peptides via engineered glycosylation. J Biol Chem. 2015;290(13):8166–8172.
[116]
ChengQ, ShiX, HanM, Smbatyan G, LenzHJ, ZhangY. Reprogramming exosomes as nanoscale controllers of cellular immunity. J Am Chem Soc. 2018;140(48):16413–16417.
[117]
LiangG, KanS, ZhuY, FengS, FengW, Gao S. Engineered exosome-mediated delivery of functionally active miR-26a and its enhanced suppression effect in HepG2 cells. Int J Nanomedicine. 2018;13:585–599.
[118]
RanN, GaoX, DongX, Li J, LinC, GengM, et al. Effects of exosome-mediated delivery of myostatin propeptide on functional recovery of mdx mice. Biomaterials. 2020;236:119826.
[119]
SrinivasanS, Vannberg FO, DixonJB. Lymphatic transport of exosomes as a rapid route of information dissemination to the lymph node. Sci Rep. 2016;6:24436.
[120]
ArmstrongJP, HolmeMN, StevensMM. Re-Engineering extracellular vesicles as smart nanoscale therapeutics. ACS Nano. 2017;11(1):69–83.
[121]
PascucciL, Coccè V, BonomiA, AmiD, Ceccarelli P, CiusaniE, et al. Paclitaxel is incorporated by mesenchymal stromal cells and released in exosomes that inhibit in vitro tumor growth: A new approach for drug delivery. J Control Release. 2014;192:262–270.
[122]
O'LoughlinAJ, Mäger I, Jong deOG, VarelaMA, Schiffelers RM, El AndaloussiS, et al. Functional delivery of lipid-conjugated siRNA by extracellular vesicles. Mol Ther. 2017;25(7):1580–1587.
[123]
ChengL, ZhangK, WuS, CuiM, XuT. Focus on mesenchymal stem cell-derived exosomes: Opportunities and challenges in cell-free therapy. Stem Cells Int. 2017;2017:6305295.
[124]
LiuC, SuC. Design strategies and application progress of therapeutic exosomes. Theranostics. 2019;9(4):1015–1028.
[125]
VillataS, CantaM, CaudaV. EVs and bioengineering: From cellular products to engineered nanomachines. Int J Mol Sci. 2020;21(17):6048.
[126]
FuhrmannG, SerioA, MazoM, Nair R, StevensMM. Active loading into extracellular vesicles significantly improves the cellular uptake and photodynamic effect of porphyrins. J Control Release. 2015;205:35–44.
[127]
NawazM, Heydarkhan-Hagvall S, TangruksaB, González-King GaribottiH, JingY, Maugeri M, et al. Lipid nanoparticles deliver the therapeutic VEGFA mRNA in vitro and in vivo and transform extracellular vesicles for their functional extensions. Adv Sci (Weinh). 2023;10(12):e2206187.
[128]
AnguelaXM, HighKA. Entering the modern era of gene therapy. Annu Rev Med. 2019;70:273–288.
[129]
LeeYS, DuttaA. MicroRNAs in cancer. Annu Rev Pathol. 2009;4:199–227.
[130]
WinkleM, El-Daly SM, FabbriM, CalinGA. Noncoding RNA therapeutics—challenges and potential solutions. Nat Rev Drug Discov. 2021;20(8):629–651.
[131]
KaraG, CalinGA, OzpolatB. RNAi-based therapeutics and tumor targeted delivery in cancer. Adv Drug Deliv Rev. 2022;182:114113.
[132]
TekedereliI, AlpaySN, AkarU, Yuca E, Ayugo-RodriguezC, HanHD, et al. Therapeutic silencing of Bcl-2 by systemically administered siRNA nanotherapeutics inhibits tumor growth by autophagy and apoptosis and enhances the efficacy of chemotherapy in orthotopic xenograft models of ER (-) and ER (+) breast cancer. Mol Ther Nucleic Acids. 2013;2(9):e121.
[133]
Reyes-GonzálezJM, Armaiz-PeñaGN, Mangala LS, ValiyevaF, IvanC, Pradeep S, et al. Targeting c-MYC in platinum-resistant ovarian cancer. Mol Cancer Ther. 2015;14(10):2260–2269.
[134]
PecotCV, WuSY, BellisterS, Filant J, RupaimooleR, HisamatsuT, et al. Therapeutic silencing of KRAS using systemically delivered siRNAs. Mol Cancer Ther. 2014;13(12):2876–2885.
[135]
AkaoY, IioA, ItohT, Noguchi S, ItohY, OhtsukiY, et al. Microvesicle-mediated RNA molecule delivery system using monocytes/macrophages. Mol Ther. 2011;19(2):395–399.
[136]
YounK, ParkJH, LeeJ, JeongWS, HoCT, JunM. The identification of biochanin A as a Potent and selective β-Site App-Cleaving Enzyme 1 (Bace1) Inhibitor. Nutrients. 2016;8(10):637.
[137]
ZhangH, WangY, BaiM, WangJ, ZhuK, LiuR, et al. Exosomes serve as nanoparticles to suppress tumor growth and angiogenesis in gastric cancer by delivering hepatocyte growth factor siRNA. Cancer Sci. 2018;109(3):629–641.
[138]
NieH, XieX, ZhangD, Zhou Y, LiB, LiF, et al. Use of lung-specific exosomes for miRNA-126 delivery in non-small cell lung cancer. Nanoscale. 2020;12(2):877–887.
[139]
OhnoS, Takanashi M, SudoK, UedaS, Ishikawa A, MatsuyamaN, et al. Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells. Mol Ther. 2013;21(1):185–191.
[140]
ZhuX, BadawiM, PomeroyS, Sutaria DS, XieZ, BaekA, et al. Comprehensive toxicity and immunogenicity studies reveal minimal effects in mice following sustained dosing of extracellular vesicles derived from HEK293T cells. J Extracell Vesicles. 2017;6(1):1324730.
[141]
SalehAF, Lázaro-Ibáñez E, ForsgardMA, ShatnyevaO, Osteikoetxea X, KarlssonF, et al. Extracellular vesicles induce minimal hepatotoxicity and immunogenicity. Nanoscale. 2019;11(14):6990–7001.
[142]
AnandP, ThomasSG, KunnumakkaraAB, SundaramC, Harikumar KB, SungB, et al. Biological activities of curcumin and its analogues (Congeners) made by man and Mother Nature. Biochem Pharmacol. 2008;76(11):1590–1611.
[143]
RavindranJ, PrasadS, AggarwalBB. Curcumin and cancer cells: How many ways can curry kill tumor cells selectively? Aaps j. 2009;11(3):495–510.
[144]
AnandP, Kunnumakkara AB, NewmanRA, AggarwalBB. Bioavailability of curcumin: Problems and promises. Mol Pharm. 2007;4(6):807–818.
[145]
SunD, ZhuangX, XiangX, Liu Y, ZhangS, LiuC, et al. A novel nanoparticle drug delivery system: The anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol Ther. 2010;18(9):1606–1614.
[146]
WangM, YuanQ, XieL. Mesenchymal stem cell-based immunomodulation: Properties and clinical application. Stem Cells Int. 2018;2018:3057624.
[147]
GomariH, Forouzandeh Moghadam M, SoleimaniM, GhavamiM, Khodashenas S. Targeted delivery of doxorubicin to HER2 positive tumor models. Int J Nanomedicine. 2019;14:5679–5690.
[148]
KimMS, HaneyMJ, ZhaoY, Mahajan V, DeygenI, KlyachkoNL, et al. Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells. Nanomedicine. 2016;12(3):655–664.
[149]
YanF, ZhongZ, WangY, Feng Y, MeiZ, LiH, et al. Exosome-based biomimetic nanoparticles targeted to inflamed joints for enhanced treatment of rheumatoid arthritis. J Nanobiotechnology. 2020;18(1):115.
[150]
VashishtM, RaniP, OnteruSK, Singh D. Curcumin encapsulated in milk exosomes resists human digestion and possesses enhanced intestinal permeability in vitro. Appl Biochem Biotechnol. 2017;183(3):993–1007.
[151]
MunagalaR, AqilF, JeyabalanJ, Gupta RC. Bovine milk-derived exosomes for drug delivery. Cancer Lett. 2016;371(1):48–61.
[152]
HanahanD, Weinberg RA. Hallmarks of cancer: The next generation. Cell. 2011;144(5):646–674.
[153]
ParralesA, Iwakuma T. Targeting oncogenic mutant p53 for cancer therapy. Front Oncol. 2015;5:288.
[154]
SettenRL, RossiJJ, HanSP. The current state and future directions of RNAi-based therapeutics. Nat Rev Drug Discov. 2019;18(6):421–446.
[155]
Roma-RodriguesC, MendesR, BaptistaPV, Fernandes AR. Targeting tumor microenvironment for cancer therapy. Int J Mol Sci. 2019;20(4):107753.
[156]
HuS, MaJ, SuC, ChenY, ShuY, QiZ, et al. Engineered exosome-like nanovesicles suppress tumor growth by reprogramming tumor microenvironment and promoting tumor ferroptosis. Acta Biomater. 2021;135:567–581.
[157]
MantovaniA, Marchesi F, MalesciA, LaghiL, Allavena P. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol. 2017;14(7):399–416.
[158]
ChanmeeT, OntongP, KonnoK, Itano N. Tumor-associated macrophages as major players in the tumor microenvironment. Cancers (Basel). 2014;6(3):1670–1690.
[159]
NonnenmacherY, HillerK. Biochemistry of proinflammatory macrophage activation. Cell Mol Life Sci. 2018;75(12):2093–2109.
[160]
KamerkarS, LengC, BurenkovaO, Jang SC, McCoyC, ZhangK, et al. Exosome-mediated genetic reprogramming of tumor-associated macrophages by exoASO-STAT6 leads to potent monotherapy antitumor activity. Sci Adv. 2022;8(7):eabj7002.
[161]
GordonS, Martinez FO. Alternative activation of macrophages: Mechanism and functions. Immunity. 2010;32(5):593–604.
[162]
DengJ, LiJ, SardeA, Lines JL, LeeYC, QianDC, et al. Hypoxia-induced VISTA promotes the suppressive function of myeloid-derived suppressor cells in the tumor microenvironment. Cancer Immunol Res. 2019;7(7):1079–1090.
[163]
ChoSH, Raybuck AL, StengelK, WeiM, BeckTC, VolanakisE, et al. Germinal centre hypoxia and regulation of antibody qualities by a hypoxia response system. Nature. 2016;537(7619):234–238.
[164]
BrandA, SingerK, KoehlGE, Kolitzus M, SchoenhammerG, ThielA, et al. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab. 2016;24(5):657–671.
[165]
WuT, LiuY, CaoY, LiuZ. Engineering macrophage exosome disguised biodegradable nanoplatform for enhanced sonodynamic therapy of glioblastoma. Adv Mater. 2022;34(15):e2110364.
[166]
PadoanA, Plebani M, BassoD. Inflammation and pancreatic cancer: Focus on metabolism, cytokines, and immunity. Int J Mol Sci. 2019;20(3):676.
[167]
De BlanderH, MorelAP, SenaratneAP, Ouzounova M, PuisieuxA. Cellular plasticity: A route to senescence exit and tumorigenesis. Cancers (Basel). 2021;13(18):4561.
[168]
JinC, Lagoudas GK, ZhaoC, BullmanS, Bhutkar A, HuB, et al. Commensal microbiota promote lung cancer development via γδ T cells. Cell. 2019;176(5):998–1013.e16.
[169]
KimMS, HaneyMJ, ZhaoY, Yuan D, DeygenI, KlyachkoNL, et al. Engineering macrophage-derived exosomes for targeted paclitaxel delivery to pulmonary metastases: In vitro and in vivo evaluations. Nanomedicine. 2018;14(1):195–204.
[170]
HuangL, RongY, TangX, Yi K, QiP, HouJ, et al. Engineered exosomes as an in situ DC-primed vaccine to boost antitumor immunity in breast cancer. Mol Cancer. 2022;21(1):45.
[171]
LvQ, ChengL, LuY, ZhangX, WangY, Deng J, et al. Thermosensitive exosome-liposome hybrid nanoparticle-mediated chemoimmunotherapy for improved treatment of metastatic peritoneal cancer. Adv Sci (Weinh). 2020;7(18):2000515.
[172]
WangJ, TangW, YangM, Yin Y, LiH, HuF, et al. Inflammatory tumor microenvironment responsive neutrophil exosomes-based drug delivery system for targeted glioma therapy. Biomaterials. 2021;273:120784.
[173]
DingB, LiT, ZhangJ, Zhao L, ZhaiG. Advances in liver-directed gene therapy for hepatocellular carcinoma by non-viral delivery systems. Curr Gene Ther. 2012;12(2):92–102.
[174]
TamuraR, UemotoS, TabataY. Augmented liver targeting of exosomes by surface modification with cationized pullulan. Acta Biomater. 2017;57:274–284.
[175]
KimH, YunN, MunD, KangJY, LeeSH, Park H, et al. Cardiac-specific delivery by cardiac tissue-targeting peptide-expressing exosomes. Biochem Biophys Res Commun. 2018;499(4):803–808.
[176]
WangX, ChenY, ZhaoZ, Meng Q, YuY, SunJ, et al. Engineered exosomes with ischemic myocardium-targeting peptide for targeted therapy in myocardial infarction. J Am Heart Assoc. 2018;7(15):e008737.
[177]
MaachaS, BhatAA, JimenezL, Raza A, HarisM, UddinS, et al. Extracellular vesicles-mediated intercellular communication: Roles in the tumor microenvironment and anti-cancer drug resistance. Mol Cancer. 2019;18(1):55.
[178]
IferganI, Scheffer GL, AssarafYG. Novel extracellular vesicles mediate an ABCG2-dependent anticancer drug sequestration and resistance. Cancer Res. 2005;65(23):10952–10958.
[179]
ZhangFF, ZhuYF, ZhaoQN, Yang DT, DongYP, JiangL, et al. Microvesicles mediate transfer of P-glycoprotein to paclitaxel-sensitive A2780 human ovarian cancer cells, conferring paclitaxel-resistance. Eur J Pharmacol. 2014;738:83–90.
[180]
LuJF, LukF, GongJ, Jaiswal R, GrauGE, BebawyM. Microparticles mediate MRP1 intercellular transfer and the re-templating of intrinsic resistance pathways. Pharmacol Res. 2013;76:77–83.
[181]
ParadaN, Romero-Trujillo A, GeorgesN, Alcayaga-MirandaF. Camouflage strategies for therapeutic exosomes evasion from phagocytosis. J Adv Res. 2021;31:61–74.
[182]
LinZ, WuY, XuY, LiG, LiZ, LiuT. Mesenchymal stem cell-derived exosomes in cancer therapy resistance: Recent advances and therapeutic potential. Mol Cancer. 2022;21(1):179.
[183]
AvgoulasDI, Tasioulis KS, PapiRM, PantazakiAA. Therapeutic and diagnostic potential of exosomes as drug delivery systems in brain cancer. Pharmaceutics. 2023;15(5):1439.
[184]
AgrawalAK, AqilF, JeyabalanJ, Spencer WA, BeckJ, GachukiBW, et al. Milk-derived exosomes for oral delivery of paclitaxel. Nanomedicine. 2017;13(5):1627–1636.
[185]
BachDH, HongJY, ParkHJ, Lee SK. The role of exosomes and miRNAs in drug-resistance of cancer cells. Int J Cancer. 2017;141(2):220–230.
[186]
MilmanN, GininiL, GilZ. Exosomes and their role in tumorigenesis and anticancer drug resistance. Drug Resist Updat. 2019;45:1–12.
[187]
PanG, LiuY, ShangL, Zhou F, YangS. EMT-associated microRNAs and their roles in cancer stemness and drug resistance. Cancer Commun (Lond). 2021;41(3):199–217.
[188]
FatemianT, OthmanI, ChowdhuryEH. Strategies and validation for siRNA-based therapeutics for the reversal of multi-drug resistance in cancer. Drug Discov Today. 2014;19(1):71–78.
[189]
MitamuraT, WatariH, WangL, Kanno H, HassanMK, MiyazakiM, et al. Downregulation of miRNA-31 induces taxane resistance in ovarian cancer cells through increase of receptor tyrosine kinase MET. Oncogenesis. 2013;2(3):e40.
[190]
KovalchukO, Filkowski J, MeservyJ, IlnytskyyY, Tryndyak VP, ChekhunVF, et al. Involvement of microRNA-451 in resistance of the MCF-7 breast cancer cells to chemotherapeutic drug doxorubicin. Mol Cancer Ther. 2008;7(7):2152–2159.
[191]
LiangG, ZhuY, AliDJ, Tian T, XuH, SiK, et al. Engineered exosomes for targeted co-delivery of miR-21 inhibitor and chemotherapeutics to reverse drug resistance in colon cancer. J Nanobiotechnology. 2020;18(1):10.
[192]
PoeckH, BeschR, MaihoeferC, Renn M, TormoD, MorskayaSS, et al. 5'-Triphosphate-siRNA: Turning gene silencing and Rig-I activation against melanoma. Nat Med. 2008;14(11):1256–1263.
[193]
LiH, YangC, ShiY, ZhaoL. Exosomes derived from siRNA against GRP78 modified bone-marrow-derived mesenchymal stem cells suppress Sorafenib resistance in hepatocellular carcinoma. J Nanobiotechnology. 2018;16(1):103.
[194]
ZhangQ, DengT, ZhangH, Zuo D, ZhuQ, BaiM, et al. Adipocyte-derived exosomal MTTP suppresses ferroptosis and promotes chemoresistance in colorectal cancer. Adv Sci (Weinh). 2022;9(28):e2203357.
[195]
ErinN, Grahovac J, BrozovicA, EfferthT. Tumor microenvironment and epithelial mesenchymal transition as targets to overcome tumor multidrug resistance. Drug Resist Updat. 2020;53:100715.
[196]
ZhaoS, XiuG, WangJ, Wen Y, LuJ, WuB, et al. Engineering exosomes derived from subcutaneous fat MSCs specially promote cartilage repair as miR-199a-3p delivery vehicles in Osteoarthritis. J Nanobiotechnology. 2023;21(1):341.
[197]
LiuJ, RenH, ZhangC, Li J, QiuQ, ZhangN, et al. Orally-delivered, cytokine-engineered extracellular vesicles for targeted treatment of inflammatory bowel disease. Small. 2023;19(50):e2304023.
[198]
KamerkarS, LeBleuVS, SugimotoH, Yang S, RuivoCF, MeloSA, et al. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature. 2017;546(7659):498–503.
[199]
ZhangZ, GuoX, GuoX, YuR, QianM, Wang S, et al. MicroRNA-29a-3p delivery via exosomes derived from engineered human mesenchymal stem cells exerts tumour suppressive effects by inhibiting migration and vasculogenic mimicry in glioma. Aging (Albany NY). 2021;13(4):5055–5068.
[200]
LiangQ, BieN, YongT, Tang K, ShiX, WeiZ, et al. The softness of tumour-cell-derived microparticles regulates their drug-delivery efficiency. Nat Biomed Eng. 2019;3(9):729–740.
[201]
LeeH, ParkH, NohGJ, Lee ES. pH-responsive hyaluronate-anchored extracellular vesicles to promote tumor-targeted drug delivery. Carbohydr Polym. 2018;202:323–333.
[202]
McAndrewsKM, XiaoF, ChronopoulosA, LeBleuVS, Kugeratski FG, KalluriR. Exosome-mediated delivery of CRISPR/Cas9 for targeting of oncogenic Kras(G12D) in pancreatic cancer. Life Sci Alliance. 2021;4(9):e202000875.
[203]
DarGH, MendesCC, KuanWL, Speciale AA, ConceiçãoM, GörgensA, et al. GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain. Nat Commun. 2021;12(1):6666.

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