3,055
Views
0
CrossRef citations to date
0
Altmetric
Review

Lipid Nanovesicle Platforms for Hepatocellular Carcinoma Precision Medicine Therapeutics: Progress and Perspectives

ORCID Icon & ORCID Icon
Article: 2313696 | Received 06 Jul 2023, Accepted 30 Jan 2024, Published online: 15 Feb 2024

References

  • Rumgay H, Arnold M, Ferlay J, Lesi O, Cabasag CJ, Vignat J, Laversanne M, McGlynn KA, Soerjomataram I. Global burden of primary liver cancer in 2020 and predictions to 2040. J Hepatol. 2022;77(6):1598–17. doi:10.1016/j.jhep.2022.08.021.
  • Singal AG, Lampertico P, Nahon P. Epidemiology and surveillance for hepatocellular carcinoma: new trends. J Hepatol. 2020;72(2):250–61. doi:10.1016/j.jhep.2019.08.025.
  • Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, Lencioni R, Koike K, Zucman-Rossi J, Finn RS. et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7(1):6. doi:10.1038/s41572-020-00240-3.
  • Galle PR, Forner A, Llovet JM, Mazzaferro V, Piscaglia F, Raoul J-L, Schirmacher P, Vilgrain V, European Association for the Study of the Liver. Electronic address eee, European association for the study of the L. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;69(1):182–236. doi:10.1016/j.jhep.2018.03.019.
  • Cheng AL, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Lim HY, Kudo M, Breder V, Merle P. et al. Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2022;76(4):862–73. doi:10.1016/j.jhep.2021.11.030.
  • Bejjani AC, Finn RS. Hepatocellular carcinoma: pick the winner—tyrosine kinase inhibitor versus immuno-oncology agent–based combinations. J Clin Oncol. 2022;40(24):2763–73. doi:10.1200/JCO.21.02605.
  • Abou-Alfa GK, Lau G, Kudo M, Chan SL, Kelley RK, Furuse J, Sukeepaisarnjaroen W, Kang Y-K, Van Dao T, De Toni EN. et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evidence. 2022;1(8):EVIDoa2100070. doi:10.1056/EVIDoa2100070.
  • Zhang G, Huang X, Xiu H, Sun Y, Chen J, Cheng G, Song Z, Peng Y, Shen Y, Wang J. et al. Extracellular vesicles: natural liver-accumulating drug delivery vehicles for the treatment of liver diseases. J Extracell Vesicles. 2020;10(2):e12030. doi:10.1002/jev2.12030.
  • Zhu Y, Shen R, Vuong I, Reynolds RA, Shears MJ, Yao ZC, Hu Y, Cho WJ, Kong J, Reddy SK. et al. Multi-step screening of DNA/lipid nanoparticles and co-delivery with siRNA to enhance and prolong gene expression. Nat Commun. 2022;13(1):4282. doi:10.1038/s41467-022-31993-y.
  • Harding JJ, Nandakumar S, Armenia J, Khalil DN, Albano M, Ly M, Shia J, Hechtman JF, Kundra R, El Dika I. et al. Prospective genotyping of hepatocellular carcinoma: clinical implications of next-generation sequencing for matching patients to targeted and immune therapies. Clin Cancer Res. 2019;25(7):2116–26. doi:10.1158/1078-0432.CCR-18-2293.
  • Rebouissou S, Nault JC. Advances in molecular classification and precision oncology in hepatocellular carcinoma. J Hepatol. 2020;72(2):215–29. doi:10.1016/j.jhep.2019.08.017.
  • Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L, Maad IB, Calderaro J, Bioulac-Sage P, Letexier M, Degos F. et al. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet. 2012;44(6):694–8. doi:10.1038/ng.2256.
  • Boyault S, Rickman DS, de Reynies A, Balabaud C, Rebouissou S, Jeannot E, Hérault A, Saric J, Belghiti J, Franco D. et al. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology. 2007;45(1):42–52. doi:10.1002/hep.21467.
  • Hoshida Y, Nijman SM, Kobayashi M, Chan JA, Brunet JP, Chiang DY, Villanueva A, Newell P, Ikeda K, Hashimoto M. et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res. 2009;69(18):7385–92. doi:10.1158/0008-5472.CAN-09-1089.
  • Sia D, Jiao Y, Martinez-Quetglas I, Kuchuk O, Villacorta-Martin C, Castro de Moura M, Putra J, Camprecios G, Bassaganyas L, Akers N. et al. Identification of an Immune-specific Class of Hepatocellular Carcinoma, Based on Molecular Features. Gastroenterology. 2017;153(3):812–26. doi:10.1053/j.gastro.2017.06.007.
  • Montironi C, Castet F, Haber PK, Pinyol R, Torres-Martin M, Torrens L, Mesropian A, Wang H, Puigvehi M, Maeda M. et al. Inflamed and non-inflamed classes of HCC: a revised immunogenomic classification. Gut. 2023;72(1):129–40. doi:10.1136/gutjnl-2021-325918.
  • Lehrich BM, Zhang J, Monga SP, Dhanasekaran R. Battle of the biopsies: role of tissue and liquid biopsy in hepatocellular carcinoma. J Hepatol. 2023. doi:10.1016/j.jhep.2023.11.030.
  • Bagchi S, Yuan R, Engleman EG. Immune checkpoint inhibitors for the treatment of cancer: clinical impact and mechanisms of response and resistance. Annu Rev Pathol. 2021;16(1):223–49. doi:10.1146/annurev-pathol-042020-042741.
  • Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Kudo M, Breder V, Merle P, Kaseb AO. et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894–905. doi:10.1056/NEJMoa1915745.
  • Qin S, Chan SL, Gu S, Bai Y, Ren Z, Lin X, Chen Z, Jia W, Jin Y, Guo Y. et al. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study. Lancet. 2023;402(10408):1133–46. doi:10.1016/S0140-6736(23)00961-3.
  • Zhu AX, Abbas AR, de Galarreta MR, Guan Y, Lu S, Koeppen H, Zhang W, Hsu C-H, He AR, Ryoo B-Y. et al. Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma. Nat Med. 2022;28(8):1599–611. doi:10.1038/s41591-022-01868-2.
  • Chen L, Zhou Q, Liu J, Zhang W. CTNNB1 alternation is a potential biomarker for immunotherapy prognosis in patients with hepatocellular carcinoma. Front Immunol. 2021;12:759565. doi:10.3389/fimmu.2021.759565.
  • Zucman-Rossi J, Villanueva A, Nault JC, Llovet JM. Genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology. 2015;149(5):1226–39 e4. doi:10.1053/j.gastro.2015.05.061.
  • Schulze K, Imbeaud S, Letouze E, Alexandrov LB, Calderaro J, Rebouissou S, Couchy G, Meiller C, Shinde J, Soysouvanh F. et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet. 2015;47(5):505–11. doi:10.1038/ng.3252.
  • Llovet JM, Montal R, Sia D, Finn RS. Molecular therapies and precision medicine for hepatocellular carcinoma. Nat Rev Clin Oncol. 2018;15(10):599–616. doi:10.1038/s41571-018-0073-4.
  • Torchilin VP. Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discov. 2005;4(2):145–60. doi:10.1038/nrd1632.
  • Samad A, Sultana Y, Aqil M. Liposomal drug delivery systems: an update review. Curr Drug Deliv. 2007;4(4):297–305. doi:10.2174/156720107782151269.
  • Vemuri S, Rhodes CT. Preparation and characterization of liposomes as therapeutic delivery systems: a review. Pharm Acta Helv. 1995;70(2):95–111. doi:10.1016/0031-6865(95)00010-7.
  • Mozafari MR. Liposomes: an overview of manufacturing techniques. Cell Mol Biol Lett. 2005;10:711–19.
  • Maruyama K, Kennel SJ, Huang L. Lipid composition is important for highly efficient target binding and retention of immunoliposomes. Proc Natl Acad Sci U S A. 1990;87(15):5744–8. doi:10.1073/pnas.87.15.5744.
  • Immordino ML, Dosio F, Cattel L. Stealth liposomes: review of the basic science, rationale, and clinical applications, existing and potential. Int J Nanomedicine. 2006;1:297–315.
  • Torchilin VP, Omelyanenko VG, Papisov MI, Bogdanov AA Jr., Trubetskoy VS, Herron JN, Gentry CA. Poly(ethylene glycol) on the liposome surface: on the mechanism of polymer-coated liposome longevity. Biochimica et Biophysica Acta (BBA) - Biomembranes. 1994;1195(1):11–20. doi:10.1016/0005-2736(94)90003-5.
  • Noble GT, Stefanick JF, Ashley JD, Kiziltepe T, Bilgicer B. Ligand-targeted liposome design: challenges and fundamental considerations. Trends Biotechnol. 2014;32(1):32–45. doi:10.1016/j.tibtech.2013.09.007.
  • Nagayasu A, Uchiyama K, Kiwada H. The size of liposomes: a factor which affects their targeting efficiency to tumors and therapeutic activity of liposomal antitumor drugs. Adv Drug Deliv Rev. 1999;40(1–2):75–87. doi:10.1016/S0169-409X(99)00041-1.
  • Akinc A, Querbes W, De S, Qin J, Frank-Kamenetsky M, Jayaprakash KN, Jayaraman M, Rajeev KG, Cantley WL, Dorkin JR. et al. Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms. Mol Ther. 2010;18(7):1357–64. doi:10.1038/mt.2010.85.
  • Kasiewicz LN, Biswas S, Beach A, Ren H, Dutta C, Mazzola AM, Rohde E, Chadwick A, Cheng C, Garcia SP. et al. GalNAc-lipid nanoparticles enable non-LDLR dependent hepatic delivery of a CRISPR base editing therapy. Nat Commun. 2023;14(1):2776. doi:10.1038/s41467-023-37465-1.
  • Suhr OB, Coelho T, Buades J, Pouget J, Conceicao I, Berk J, Schmidt H, Waddington-Cruz M, Campistol JM, Bettencourt BR. et al. Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study. Orphanet J Rare Dis. 2015;10(1):109. doi:10.1186/s13023-015-0326-6.
  • Tabernero J, Shapiro GI, LoRusso PM, Cervantes A, Schwartz GK, Weiss GJ, Paz-Ares L, Cho DC, Infante JR, Alsina M. et al. First-in-humans trial of an RNA interference therapeutic targeting VEGF and KSP in cancer patients with liver involvement. Cancer Discov. 2013;3(4):406–17. doi:10.1158/2159-8290.CD-12-0429.
  • Wilson RC, Doudna JA. Molecular mechanisms of RNA interference. Annu Rev Biophys. 2013;42(1):217–39. doi:10.1146/annurev-biophys-083012-130404.
  • Castanotto D, Rossi JJ. The promises and pitfalls of RNA-interference-based therapeutics. Nature. 2009;457(7228):426–33. doi:10.1038/nature07758.
  • Pai SI, Lin YY, Macaes B, Meneshian A, Hung CF, Wu TC. Prospects of RNA interference therapy for cancer. Gene Ther. 2006;13(6):464–77. doi:10.1038/sj.gt.3302694.
  • Hou B, Qin L, Huang L. Liver cancer cells as the model for developing liver-targeted RNAi therapeutics. Biochem Biophys Res Commun. 2023;644:85–94. doi:10.1016/j.bbrc.2023.01.007.
  • Zhong J, Huang HL, Li J, Qian FC, Li LQ, Niu PP, Dai L-C. Development of hybrid-type modified chitosan derivative nanoparticles for the intracellular delivery of midkine-siRNA in hepatocellular carcinoma cells. Hepatobiliary Pancreat Dis Int. 2015;14(1):82–89. doi:10.1016/S1499-3872(15)60336-8.
  • Younis MA, Khalil IA, Abd Elwakil MM, Harashima H. A multifunctional lipid-based nanodevice for the highly specific codelivery of Sorafenib and Midkine siRNA to hepatic cancer cells. Mol Pharm. 2019;16(9):4031–44. doi:10.1021/acs.molpharmaceut.9b00738.
  • Younis MA, Khalil IA, Elewa YHA, Kon Y, Harashima H. Ultra-small lipid nanoparticles encapsulating sorafenib and midkine-siRNA selectively-eradicate sorafenib-resistant hepatocellular carcinoma in vivo. J Control Release. 2021;331:335–49. doi:10.1016/j.jconrel.2021.01.021.
  • Woitok MM, Zoubek ME, Doleschel D, Bartneck M, Mohamed MR, Kiessling F, Lederle W, Trautwein C, Cubero FJ. Lipid-encapsulated siRNA for hepatocyte-directed treatment of advanced liver disease. Cell Death Disease. 2020;11(5):343. doi:10.1038/s41419-020-2571-4.
  • Fitamant J, Kottakis F, Benhamouche S, Tian HS, Chuvin N, Parachoniak CA, Nagle J, Perera R, Lapouge M, Deshpande V. et al. YAP inhibition restores hepatocyte differentiation in advanced HCC, leading to tumor Regression. Cell Rep. 2015;10(10):1692–707. doi:10.1016/j.celrep.2015.02.027.
  • Huang KW, Hsu FF, Qiu JT, Chern GJ, Lee YA, Chang CC, Huang Y-T, Sung Y-C, Chiang C-C, Huang R-L. et al. Highly efficient and tumor-selective nanoparticles for dual-targeted immunogene therapy against cancer. Sci Adv. 2020;6(3):eaax5032. doi:10.1126/sciadv.aax5032.
  • Song C, Zhang J, Wen R, Li Q, Zhou J, Xiaoli L, Wu Z, Lv Y, Wu R. Improved anti-hepatocellular carcinoma effect by enhanced Co-delivery of Tim-3 siRNA and sorafenib via multiple pH triggered drug-eluting nanoparticles. Mater Today Bio. 2022;16:100350. doi:10.1016/j.mtbio.2022.100350.
  • Yao Y, Wang T, Liu Y, Zhang N. Co-delivery of sorafenib and VEGF-siRNA via pH-sensitive liposomes for the synergistic treatment of hepatocellular carcinoma. Artif Cells, Nanomed Biotechnol. 2019;47(1):1374–83. doi:10.1080/21691401.2019.1596943.
  • Punuch K, Wongwan C, Jantana S, Somboonyosdech C, Rodponthukwaji K, Kunwong N, Nguyen KT, Sirivatanauksorn V, Sirivatanauksorn Y, Srisawat C. et al. Study of siRNA delivery via polymeric nanoparticles in combination with angiogenesis inhibitor for the treatment of AFP-Related liver cancer. Int J Mol Sci. 2022;23(20):23. doi:10.3390/ijms232012666.
  • Jamal F, Ahmed G, Farazuddin M, Altaf I, Farheen S, Zia Q, Azhar A, Ahmad H, Khan AA, Somavarapu S. et al. Potential of siRNA-bearing subtilosomes in the treatment of diethylnitrosamine-induced hepatocellular carcinoma. Molecules. 2023;28(5):28. doi:10.3390/molecules28052191.
  • Chen Y, Zhao D, Xiao F, Li X, Li J, Su Z, Jiang X. Microfluidics-enabled Serial Assembly of Lipid-siRNA-sorafenib Nanoparticles for Synergetic Hepatocellular Carcinoma Therapy. Adv Mater. 2023;35(13):e2209672. doi:10.1002/adma.202209672.
  • Wang L, Zhu L, Liang C, Huang X, Liu Z, Huo J, Zhang Y, Zhang Y, Chen L, Xu H. et al. Targeting N6-methyladenosine reader YTHDF1 with siRNA boosts antitumor immunity in NASH-HCC by inhibiting EZH2-IL-6 axis. J Hepatol. 2023;79(5):1185–200. doi:10.1016/j.jhep.2023.06.021.
  • Zhao P, Li M, Wang Y, Chen Y, He C, Zhang X, Yang T, Lu Y, You J, Lee RJ. et al. Enhancing anti-tumor efficiency in hepatocellular carcinoma through the autophagy inhibition by miR-375/sorafenib in lipid-coated calcium carbonate nanoparticles. Acta Biomater. 2018;72:248–55. doi:10.1016/j.actbio.2018.03.022.
  • Lai I, Swaminathan S, Baylot V, Mosley A, Dhanasekaran R, Gabay M, Felsher DW. Lipid nanoparticles that deliver IL-12 messenger RNA suppress tumorigenesis in MYC oncogene-driven hepatocellular carcinoma. J Immunother Cancer. 2018;6(1):125. doi:10.1186/s40425-018-0431-x.
  • Deng Z, Yang H, Tian Y, Liu Z, Sun F, Yang P. An OX40L mRNA vaccine inhibits the growth of hepatocellular carcinoma. Front Oncol. 2022;12:975408. doi:10.3389/fonc.2022.975408.
  • Liu JY, Chiang T, Liu CH, Chern GG, Lin TT, Gao DY, Chen Y. Delivery of siRNA using CXCR4-targeted nanoparticles modulates tumor microenvironment and achieves a potent antitumor response in liver cancer. Mol Ther. 2015;23(11):1772–82. doi:10.1038/mt.2015.147.
  • Gao DY, Lin Ts T, Sung YC, Liu YC, Chiang WH, Chang CC, Liu J-Y, Chen Y. CXCR4-targeted lipid-coated PLGA nanoparticles deliver sorafenib and overcome acquired drug resistance in liver cancer. Biomaterials. 2015;67:194–203. doi:10.1016/j.biomaterials.2015.07.035.
  • Zheng N, Liu W, Li B, Nie H, Liu J, Cheng Y, Wang J, Dong H, Jia L. Co-delivery of sorafenib and metapristone encapsulated by CXCR4-targeted PLGA-PEG nanoparticles overcomes hepatocellular carcinoma resistance to sorafenib. J Exp Clin Cancer Res. 2019;38(1):232. doi:10.1186/s13046-019-1216-x.
  • Ganesh S, Koser ML, Cyr WA, Chopda GR, Tao J, Shui X, Ying B, Chen D, Pandya P, Chipumuro E. et al. Direct pharmacological inhibition of β-catenin by RNA interference in tumors of diverse origin. Mol Cancer Ther. 2016;15(9):2143–54. doi:10.1158/1535-7163.MCT-16-0309.
  • Tao J, Zhang R, Singh S, Poddar M, Xu E, Oertel M, Chen X, Ganesh S, Abrams M, Monga SP. et al. Targeting β-catenin in hepatocellular cancers induced by coexpression of mutant β-catenin and K-Ras in mice. Hepatology. 2017;65(5):1581–99. doi:10.1002/hep.28975.
  • Kim M, Jeong M, Hur S, Cho Y, Park J, Jung H, Seo Y, Woo HA, Nam KT, Lee K. et al. Engineered ionizable lipid nanoparticles for targeted delivery of RNA therapeutics into different types of cells in the liver. Sci Adv. 2021;7(9). doi:10.1126/sciadv.abf4398.
  • Peng Y, Su Z, Wang X, Wu T, Xiao H, Shuai X, Lan Y. Near-infrared light laser-triggered release of doxorubicin and sorafenib from TemperatureSensitive liposomes for synergistic therapy of hepatocellular carcinoma. J Biomed Nanotechnol. 2020;16(9):1381–93. doi:10.1166/jbn.2020.2975.
  • Li Y, Miao Y, Chen M, Chen X, Li F, Zhang X, Gan Y. Stepwise targeting and responsive lipid-coated nanoparticles for enhanced tumor cell sensitivity and hepatocellular carcinoma therapy. Theranostics. 2020;10(8):3722–36. doi:10.7150/thno.42008.
  • Su Y, Zhang Z, Lee LTO, Peng L, Lu L, He X, Zhang X. Amphiphilic dendrimer doping enhanced pH-sensitivity of liposomal vesicle for effective Co-delivery toward synergistic ferroptosis–apoptosis therapy of hepatocellular carcinoma. Adv Healthcare Mater. 2023;12(6):e2202663. doi:10.1002/adhm.202202663.
  • Mahmoud K, Swidan S, El-Nabarawi M, Teaima M. Lipid based nanoparticles as a novel treatment modality for hepatocellular carcinoma: a comprehensive review on targeting and recent advances. J Nanobiotechnology. 2022;20(1):109. doi:10.1186/s12951-022-01309-9.
  • van Niel G, D’Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018;19(4):213–28. doi:10.1038/nrm.2017.125.
  • Mulcahy LA, Pink RC, Carter DR. Routes and mechanisms of extracellular vesicle uptake. J Extracell Vesicles. 2014;3(1). doi:10.3402/jev.v3.24641.
  • Cheng L, Hill AF. Therapeutically harnessing extracellular vesicles. Nat Rev Drug Discov. 2022;21(5):379–99. doi:10.1038/s41573-022-00410-w.
  • Murphy DE, de Jong OG, Brouwer M, Wood MJ, Lavieu G, Schiffelers RM, Vader P. Extracellular vesicle-based therapeutics: natural versus engineered targeting and trafficking. Experimental & Molecular Medicine. 2019;51(3):1–12. doi:10.1038/s12276-019-0223-5.
  • Claridge B, Lozano J, Poh QH, Greening DW. Development of extracellular vesicle therapeutics: challenges, considerations, and opportunities. Front Cell Dev Biol. 2021;9:734720. doi:10.3389/fcell.2021.734720.
  • Esmaeili A, Alini M, Baghaban Eslaminejad M, Hosseini S. Engineering strategies for customizing extracellular vesicle uptake in a therapeutic context. Stem Cell Res Ther. 2022;13(1):129. doi:10.1186/s13287-022-02806-2.
  • Nedeva C, Mathivanan S. Engineering Extracellular Vesicles for Cancer Therapy. Subcell Biochem. 2021;97:375–92.
  • Deng J, Ke H. Overcoming the resistance of hepatocellular carcinoma to PD-1/PD-L1 inhibitor and the resultant immunosuppression by CD38 siRNA-loaded extracellular vesicles. Oncoimmunology. 2023;12(1):2152635. doi:10.1080/2162402X.2022.2152635.
  • HHM N, Lee RY, Goh S, Tay ISY, Lim X, Lee B, Chew V, Li H, Tan B, Lim S. et al. Immunohistochemical scoring of CD38 in the tumor microenvironment predicts responsiveness to anti-PD-1/PD-L1 immunotherapy in hepatocellular carcinoma. J Immunother Cancer. 2020;8(2):e000987. doi:10.1136/jitc-2020-000987.
  • Li X, Yu Q, Zhao R, Guo X, Liu C, Zhang K, Zhang W, Liu J, Yu J, Wang S. et al. Designer exosomes for targeted delivery of a novel therapeutic cargo to enhance sorafenib-mediated ferroptosis in hepatocellular carcinoma. Front Oncol. 2022;12:898156. doi:10.3389/fonc.2022.898156.
  • Zhou X, Miao Y, Wang Y, He S, Guo L, Mao J, Chen M, Yang Y, Zhang X, Gan Y. et al. Tumour-derived extracellular vesicle membrane hybrid lipid nanovesicles enhance siRNA delivery by tumour-homing and intracellular freeway transportation. J Extracell Vesicles. 2022;11(3):e12198. doi:10.1002/jev2.12198.
  • Kamerkar S, Leng C, Burenkova O, Jang SC, McCoy C, Zhang K, Dooley K, Kasera S, Zi T, Sisó S. 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. doi:10.1126/sciadv.abj7002.
  • Gunassekaran GR, Poongkavithai Vadevoo SM, Baek MC, Lee B. M1 macrophage exosomes engineered to foster M1 polarization and target the IL-4 receptor inhibit tumor growth by reprogramming tumor-associated macrophages into M1-like macrophages. Biomaterials. 2021;278:121137. doi:10.1016/j.biomaterials.2021.121137.
  • Matsuda A, Ishiguro K, Yan IK, Patel T. Extracellular Vesicle-Based Therapeutic Targeting of β-Catenin to Modulate Anticancer Immune Responses in Hepatocellular Cancer. Hepatol Commun. 2019;3(4):525–41. doi:10.1002/hep4.1311.
  • Ishiguro K, Yan IK, Lewis-Tuffin L, Patel T. Targeting liver cancer stem cells using engineered biological nanoparticles for the treatment of hepatocellular cancer. Hepatol Commun. 2020;4(2):298–313. doi:10.1002/hep4.1462.
  • Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRnas and microRnas is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9(6):654–9. doi:10.1038/ncb1596.
  • Skog J, Wurdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, Carter BS, Krichevsky AM, Breakefield XO. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol. 2008;10(12):1470–76. doi:10.1038/ncb1800.
  • Reshke R, Taylor JA, Savard A, Guo H, Rhym LH, Kowalski PS, Trung MT, Campbell C, Little W, Anderson DG. et al. Reduction of the therapeutic dose of silencing RNA by packaging it in extracellular vesicles via a pre-microRNA backbone. Nat Biomed Eng. 2020;4(1):52–68. doi:10.1038/s41551-019-0502-4.
  • Morishita A, Oura K, Tadokoro T, Fujita K, Tani J, Masaki T. MicroRNAs in the pathogenesis of hepatocellular carcinoma: a review. Cancers Basel. 2021;13(3):514. doi:10.3390/cancers13030514.
  • Li W, Xie L, He X, Li J, Tu K, Wei L, Wu J, Guo Y, Ma X, Zhang P. et al. Diagnostic and prognostic implications of microRNAs in human hepatocellular carcinoma. Int J Cancer. 2008;123(7):1616–22. doi:10.1002/ijc.23693.
  • Baldari S, Di Rocco G, Magenta A, Picozza M, Toietta G. Extracellular vesicles–encapsulated MicroRNA-125b produced in genetically modified mesenchymal stromal cells inhibits hepatocellular carcinoma cell proliferation. Cells. 2019;8(12):1560. doi:10.3390/cells8121560.
  • Mahati S, Fu X, Ma X, Zhang H, Xiao L. Delivery of miR-26a using an exosomes-based nanosystem inhibited proliferation of hepatocellular carcinoma. Front Mol Biosci. 2021;8:738219. doi:10.3389/fmolb.2021.738219.
  • Ellipilli S, Wang H, Binzel DW, Shu D, Guo P. Ligand-displaying-exosomes using RNA nanotechnology for targeted delivery of multi-specific drugs for liver cancer regression. Nanomedicine. 2023;50:102667. doi:10.1016/j.nano.2023.102667.
  • Walker S, Busatto S, Pham A, Tian M, Suh A, Carson K, Quintero A, Lafrence M, Malik H, Santana MX. et al. Extracellular vesicle-based drug delivery systems for cancer treatment. Theranostics. 2019;9(26):8001–17. doi:10.7150/thno.37097.
  • Haney MJ, Klyachko NL, Zhao Y, Gupta R, Plotnikova EG, He Z, Patel T, Piroyan A, Sokolsky M, Kabanov AV. et al. Exosomes as drug delivery vehicles for Parkinson’s disease therapy. J Control Release. 2015;207:18–30. doi:10.1016/j.jconrel.2015.03.033.
  • Busatto S, Iannotta D, Walker SA, Di Marzio L, Wolfram J. A simple and quick method for loading proteins in extracellular vesicles. Pharm (Basel). 2021;14(4):14. doi:10.3390/ph14040356.
  • Han Y, Jones TW, Dutta S, Zhu Y, Wang X, Narayanan SP, Fagan SC, Zhang D. Overview and update on methods for cargo loading into extracellular vesicles. Processes (Basel). 2021;9(2):356. doi:10.3390/pr9020356.
  • Cheng Q, Dai Z, Smbatyan G, Epstein AL, Lenz HJ, Zhang Y. Eliciting anti-cancer immunity by genetically engineered multifunctional exosomes. Mol Ther. 2022;30(9):3066–77. doi:10.1016/j.ymthe.2022.06.013.
  • Zhang J, Song H, Dong Y, Li G, Li J, Cai Q, Yuan S, Wang Y, Song H. Surface engineering of HEK293 cell-derived extracellular vesicles for improved pharmacokinetic profile and targeted delivery of IL-12 for the treatment of hepatocellular carcinoma. Int J Nanomedicine. 2023;18:209–23. doi:10.2147/IJN.S388916.
  • Kooijmans SAA, Stremersch S, Braeckmans K, de Smedt SC, Hendrix A, Wood MJA, Schiffelers RM, Raemdonck K, Vader P. Electroporation-induced siRNA precipitation obscures the efficiency of siRNA loading into extracellular vesicles. J Control Release. 2013;172(1):229–38. doi:10.1016/j.jconrel.2013.08.014.
  • Ilahibaks NF, Ardisasmita AI, Xie S, Gunnarsson A, Brealey J, Vader P, de Jong OG, de Jager S, Dekker N, Peacock B. et al. TOP-EVs: technology of protein delivery through extracellular vesicles is a versatile platform for intracellular protein delivery. J Control Release. 2023;355:579–92. doi:10.1016/j.jconrel.2023.02.003.
  • Somiya M, Kuroda S. Engineering of extracellular vesicles for small molecule-regulated cargo loading and cytoplasmic delivery of bioactive proteins. Mol Pharm. 2022;19(7):2495–505. doi:10.1021/acs.molpharmaceut.2c00192.
  • Yang C, Guan Z, Pang X, Tan Z, Yang X, Li X, Guan F. Desialylated mesenchymal stem cells-derived extracellular vesicles loaded with doxorubicin for targeted inhibition of hepatocellular carcinoma. Cells. 2022;11(17):2642. doi:10.3390/cells11172642.
  • Liang L, Zhao L, Wang Y, Wang Y. Treatment for hepatocellular carcinoma is enhanced when norcantharidin is encapsulated in exosomes derived from bone marrow mesenchymal stem cells. Mol Pharm. 2021;18(3):1003–13. doi:10.1021/acs.molpharmaceut.0c00976.
  • Mo J, Da X, Li Q, Huang J, Lu L, Lu H. The study of exosomes-encapsulated mPEG-PLGA polymer drug-loaded particles for targeted therapy of liver cancer. J Oncol. 2022;2022:4234116. doi:10.1155/2022/4234116.
  • Wan T, Zhong J, Pan Q, Zhou T, Ping Y, Liu X. Exosome-mediated delivery of Cas9 ribonucleoprotein complexes for tissue-specific gene therapy of liver diseases. Sci Adv. 2022;8(37):eabp9435. doi:10.1126/sciadv.abp9435.
  • Zhuang J, Tan J, Wu C, Zhang J, Liu T, Fan C, Li J, Zhang Y. Extracellular vesicles engineered with valency-controlled DNA nanostructures deliver CRISPR/Cas9 system for gene therapy. Nucleic Acids Res. 2020;48(16):8870–82. doi:10.1093/nar/gkaa683.
  • Chen R, Huang H, Liu H, Xi J, Ning J, Zeng W, Shen C, Zhang T, Yu G, Xu Q. et al. Friend or foe? Evidence indicates endogenous exosomes can deliver functional gRNA and Cas9 protein. Small. 2019;15(38):e1902686. doi:10.1002/smll.201902686.
  • Rolling F, Samulski RJ. AAV as a viral vector for human gene therapy. Generation of recombinant virus. Mol Biotechnol. 1995;3(1):9–15. doi:10.1007/BF02821330.
  • Hudry E, Martin C, Gandhi S, Gyorgy B, Scheffer DI, Mu D, Merkel SF, Mingozzi F, Fitzpatrick Z, Dimant H. et al. Exosome-associated AAV vector as a robust and convenient neuroscience tool. Gene Ther. 2016;23(4):380–92. doi:10.1038/gt.2016.11.
  • Gyorgy B, Fitzpatrick Z, Crommentuijn MH, Mu D, Maguire CA. Naturally enveloped AAV vectors for shielding neutralizing antibodies and robust gene delivery in vivo. Biomaterials. 2014;35(26):7598–609. doi:10.1016/j.biomaterials.2014.05.032.
  • Liu B, Li Z, Huang S, Yan B, He S, Chen F, Liang Y. AAV-Containing exosomes as a novel vector for improved gene delivery to lung cancer cells. Front Cell Dev Biol. 2021;9:707607. doi:10.3389/fcell.2021.707607.
  • Khan N, Maurya S, Bammidi S, Jayandharan GR. AAV6 Vexosomes Mediate Robust Suicide Gene Delivery in a Murine Model of Hepatocellular Carcinoma. Mol Ther Methods Clin Dev. 2020;17:497–504. doi:10.1016/j.omtm.2020.03.006.
  • Kim HY, Min HK, Song HW, Yoo A, Lee S, Kim KP, Park J-O, Choi YH, Choi E. Delivery of human natural killer cell-derived exosomes for liver cancer therapy: an in vivo study in subcutaneous and orthotopic animal models. Drug Deliv. 2022;29(1):2897–911. doi:10.1080/10717544.2022.2118898.
  • Wu B, Feng J, Guo J, Wang J, Xiu G, Xu J, Ning K, Ling B, Fu Q, Xu J. et al. Adscs-derived exosomes ameliorate hepatic fibrosis by suppressing stellate cell activation and remodeling hepatocellular glutamine synthetase-mediated glutamine and ammonia homeostasis. Stem Cell Res Ther. 2022;13(1):494. doi:10.1186/s13287-022-03049-x.
  • de Galarreta M R, Bresnahan E, Molina-Sanchez P, Lindblad KE, Maier B, Sia D, Puigvehi M, Miguela V, Casanova-Acebes M, Dhainaut M. et al. β-Catenin Activation Promotes Immune Escape and Resistance to Anti–PD-1 Therapy in Hepatocellular Carcinoma. Cancer Discov. 2019;9(8):1124–41. doi:10.1158/2159-8290.CD-19-0074.
  • Lu Z, Zuo B, Jing R, Gao X, Rao Q, Liu Z, Qi H, Guo H, Yin H. Dendritic cell-derived exosomes elicit tumor regression in autochthonous hepatocellular carcinoma mouse models. J Hepatol. 2017;67(4):739–48. doi:10.1016/j.jhep.2017.05.019.
  • Meng M, Zhang X, Li Q, Han J, Chen Y, Qiao H, Yang Y, Huang X. Engineering M1-derived nanovesicles loading with docosahexaenoic acid synergizes ferroptosis and immune activation for treating hepatocellular carcinoma. Cancer Nanotechnol. 2023;14(1):17. doi:10.1186/s12645-023-00166-x.
  • Villa A, Garofalo M, Crescenti D, Rizzi N, Brunialti E, Vingiani A, Belotti P, Sposito C, Franzè S, Cilurzo F. et al. Transplantation of autologous extracellular vesicles for cancer-specific targeting. Theranostics. 2021;11(5):2034–47. doi:10.7150/thno.51344.
  • Herrmann IK, Wood MJA, Fuhrmann G. Extracellular vesicles as a next-generation drug delivery platform. Nat Nanotechnol. 2021;16(7):748–59. doi:10.1038/s41565-021-00931-2.
  • Rohde E, Pachler K, Gimona M. Manufacturing and characterization of extracellular vesicles from umbilical cord–derived mesenchymal stromal cells for clinical testing. Cytotherapy. 2019;21(6):581–92. doi:10.1016/j.jcyt.2018.12.006.
  • Lener T, Gimona M, Aigner L, Borger V, Buzas E, Camussi G, Chaput N, Chatterjee D, Court FA, Del Portillo HA. et al. Applying extracellular vesicles based therapeutics in clinical trials – an ISEV position paper. J Extracell Vesicles. 2015;4(1):30087. doi:10.3402/jev.v4.30087.
  • Lehrich BM, Liang Y, Fiandaca MS. Foetal bovine serum influence on in vitro extracellular vesicle analyses. J Extracell Vesicles. 2021;10(3):e12061. doi:10.1002/jev2.12061.
  • Lehrich BM, Liang Y, Khosravi P, Federoff HJ, Fiandaca MS. Fetal Bovine Serum-Derived Extracellular Vesicles Persist within Vesicle-Depleted Culture Media. Int J Mol Sci. 2018;19(11):3538. doi:10.3390/ijms19113538.
  • Patel DB, Gray KM, Santharam Y, Lamichhane TN, Stroka KM, Jay SM. Impact of cell culture parameters on production and vascularization bioactivity of mesenchymal stem cell-derived extracellular vesicles. Bioeng Transl Med. 2017;2(2):170–79. doi:10.1002/btm2.10065.
  • Lee YXF, Johansson H, Wood MJA, El Andaloussi S. Considerations and implications in the purification of extracellular vesicles - a cautionary tale. Front Neurosci. 2019;13:1067. doi:10.3389/fnins.2019.01067.
  • Liang Y, Lehrich BM, Zheng S, Lu M. Emerging methods in biomarker identification for extracellular vesicle-based liquid biopsy. J Extracell Vesicles. 2021;10(7):e12090. doi:10.1002/jev2.12090.
  • Chen VL, Xu D, Wicha MS, Lok AS, Parikh ND. Utility of liquid biopsy analysis in detection of hepatocellular Carcinoma, determination of prognosis, and disease monitoring: a systematic review. Clin Gastroenterol Hepatol. 2020;18(13):2879–902 e9. doi:10.1016/j.cgh.2020.04.019.
  • Li Y, Wu J, Li E, Xiao Z, Lei J, Zhou F, Yin X, Hu D, Mao Y, Wu L. et al. TP53 mutation detected in circulating exosomal DNA is associated with prognosis of patients with hepatocellular carcinoma. Cancer Biol Ther. 2022;23(1):439–45. doi:10.1080/15384047.2022.2094666.
  • Wang P, Song Q, Ren J, Zhang W, Wang Y, Zhou L, Wang D, Chen K, Jiang L, Zhang B. et al. Simultaneous analysis of mutations and methylations in circulating cell-free DNA for hepatocellular carcinoma detection. Sci Transl Med. 2022;14(672):eabp8704. doi:10.1126/scitranslmed.abp8704.
  • Phan TH, Chi Nguyen VT, Thi Pham TT, Nguyen VC, Ho TD, Quynh Pham TM, Tran T-H, Nguyen TD, Khang Le ND, Nguyen T-H. et al. Circulating DNA methylation profile improves the accuracy of serum biomarkers for the detection of nonmetastatic hepatocellular carcinoma. Future Oncol. 2022;18(39):4399–413. doi:10.2217/fon-2022-1218.
  • Sun N, Lee YT, Zhang RY, Kao R, Teng PC, Yang Y, Yang P, Wang JJ, Smalley M, Chen P-J. et al. Purification of HCC-specific extracellular vesicles on nanosubstrates for early HCC detection by digital scoring. Nat Commun. 2020;11(1):4489. doi:10.1038/s41467-020-18311-0.
  • Kim SS, Baek GO, Son JA, Ahn HR, Yoon MK, Cho HJ, Yoon JH, Nam SW, Cheong JY, Eun JW. et al. Early detection of hepatocellular carcinoma via liquid biopsy: panel of small extracellular vesicle-derived long noncoding RNAs identified as markers. Mol Oncol. 2021;15(10):2715–31. doi:10.1002/1878-0261.13049.
  • Shuen TWH, Alunni-Fabbroni M, Ocal E, Malfertheiner P, Wildgruber M, Schinner R, Pech M, Benckert J, Sangro B, Kuhl C. et al. Extracellular vesicles may predict response to radioembolization and Sorafenib treatment in advanced hepatocellular carcinoma: an exploratory analysis from the SORAMIC trial. Clin Cancer Res. 2022;28(17):3890–901. doi:10.1158/1078-0432.CCR-22-0569.
  • Sun N, Zhang C, Lee YT, Tran BV, Wang J, Kim H, Lee J, Zhang RY, Wang JJ, Hu J. et al. HCC EV ECG score: an extracellular vesicle-based protein assay for detection of early-stage hepatocellular carcinoma. Hepatology. 2023;77(3):774–88. doi:10.1002/hep.32692.
  • Rodriguez-Rivera II, Wu T-H, Ciotti R, Senapedis W, Sullivan K, Gao JZ, Palakurthi S, McCauley T, Moore Y. A phase 1/2 open-label study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of OTX-2002 as a single agent and in combination with standard of care in patients with hepatocellular carcinoma and other solid tumor types known for association with the MYC oncogene (MYCHELANGELO I). J Clin Oncol. 2023;41:TPS627–TPS.
  • CancerNetwork. OTX-2002 shows encouraging safety in small hepatocellular carcinoma cohort. 2023.
  • Bottger R, Pauli G, Chao PH, Al Fayez N, Hohenwarter L, Li SD. Lipid-based nanoparticle technologies for liver targeting. Adv Drug Deliv Rev. 2020;154-155:79–101. doi:10.1016/j.addr.2020.06.017.
  • Akinc A, Maier MA, Manoharan M, Fitzgerald K, Jayaraman M, Barros S, Ansell S, Du X, Hope MJ, Madden TD. et al. The Onpattro story and the clinical translation of nanomedicines containing nucleic acid-based drugs. Nat Nanotechnol. 2019;14(12):1084–7. doi:10.1038/s41565-019-0591-y.
  • Gubernator J. Active methods of drug loading into liposomes: recent strategies for stable drug entrapment and increased in vivo activity. Expert Opin Drug Deliv. 2011;8(5):565–80. doi:10.1517/17425247.2011.566552.
  • Kalita T, Dezfouli SA, Pandey LM, Uludag H. siRNA functionalized lipid nanoparticles (LNPs) in management of diseases. Pharmaceutics. 2022;14(11):14. doi:10.3390/pharmaceutics14112520.