Encapsulation of Nano-Bortezomib in Apoptotic Stem Cell-Derived Vesicles for the Treatment of Multiple Myeloma.

Extracellular vesicles (EVs) are lipid bilayer nanovesicles released from living or apoptotic cells that can transport DNA, RNA, protein, and lipid cargo. EVs play critical roles in cell-cell communication and tissue homeostasis, and have numerous therapeutic uses including serving as carriers for nanodrug delivery. There are multiple ways to load EVs with nanodrugs, such as electroporation, extrusion, and ultrasound. However, these approaches may have limited drug-loading rates, poor EV membrane stability, and high cost for large-scale production. Here, it is shown that apoptotic mesenchymal stem cells (MSCs) can encapsulate exogenously added nanoparticles into apoptotic vesicles (apoVs) with a high loading efficiency. When nano-bortezomib is incorporated into apoVs in culture-expanded apoptotic MSCs, nano-bortezomib-apoVs show a synergistic combination effect of bortezomib and apoVs to ameliorate multiple myeloma (MM) in a mouse model, along with significantly reduced side effects of nano-bortezomib. Moreover, it is shown that Rab7 regulates the nanoparticle encapsulation efficiency in apoptotic MSCs and that activation of Rab7 can increase nanoparticle-apoV production. In this study, a previously unknown mechanism to naturally synthesize nano-bortezomib-apoVs to improve MM therapy is revealed.

[1]  R. Kholodenko,et al.  Resistance of Human Liver Mesenchymal Stem Cells to FAS-Induced Cell Death , 2022, Current issues in molecular biology.

[2]  S. Shi,et al.  Proteomic analysis of MSC‐derived apoptotic vesicles identifies Fas inheritance to ameliorate haemophilia a via activating platelet functions , 2022, Journal of extracellular vesicles.

[3]  S. Rajkumar,et al.  Multiple myeloma: 2022 update on diagnosis, risk stratification, and management , 2022, American journal of hematology.

[4]  S. Shi,et al.  Electrostatic Charge-Mediated Apoptotic Vesicle Biodistribution Attenuates Sepsis by Switching Neutrophil NETosis to Apoptosis. , 2022, Small.

[5]  E. Candi,et al.  The secretion profile of mesenchymal stem cells and potential applications in treating human diseases , 2022, Signal Transduction and Targeted Therapy.

[6]  S. Inoue,et al.  Expression and localization of CD63 in the intracellular vesicles of odontoblasts , 2022, Histochemistry and Cell Biology.

[7]  Xiawei Wei,et al.  Mesenchymal stem/stromal cells in cancer therapy , 2021, Journal of Hematology & Oncology.

[8]  S. Shi,et al.  Apoptotic Extracellular Vesicles Ameliorate Multiple Myeloma by Restoring Fas-Mediated Apoptosis. , 2021, ACS nano.

[9]  Longjiang Li,et al.  Therapeutic roles of mesenchymal stem cell-derived extracellular vesicles in cancer , 2021, Journal of Hematology & Oncology.

[10]  W. Liu,et al.  RAB7 activity is required for the regulation of mitophagy in oocyte meiosis and oocyte quality control during ovarian aging , 2021, Autophagy.

[11]  D. Mooney,et al.  Obstacles and opportunities in a forward vision for cancer nanomedicine , 2021, Nature Materials.

[12]  M. J. Wood,et al.  Extracellular vesicles as a next-generation drug delivery platform , 2021, Nature Nanotechnology.

[13]  H. Einsele,et al.  Cereblon Enhancer Methylation and IMiD Resistance in Multiple Myeloma. , 2021, Blood.

[14]  Yan Jin,et al.  Apoptotic vesicles restore liver macrophage homeostasis to counteract type 2 diabetes , 2021, Journal of extracellular vesicles.

[15]  Yue Cao,et al.  An ESCRT-dependent step in fatty acid transfer from lipid droplets to mitochondria through VPS13D−TSG101 interactions , 2021, Nature communications.

[16]  D. Pei,et al.  Challenges and advances in clinical applications of mesenchymal stromal cells , 2021, Journal of Hematology & Oncology.

[17]  Jianli Wang,et al.  Extracellular vesicles: Natural liver‐accumulating drug delivery vehicles for the treatment of liver diseases , 2020, Journal of extracellular vesicles.

[18]  K. Billiar,et al.  Mechanical Regulation of Apoptosis in the Cardiovascular System , 2020, Annals of Biomedical Engineering.

[19]  H. Qian,et al.  Extracellular vesicles: A bright star of nanomedicine. , 2020, Biomaterials.

[20]  H. Barrera-Saldana,et al.  Mesenchymal Stem Cells Current Clinical Applications: A Systematic Review. , 2020, Archives of medical research.

[21]  Nathaniel H. Park,et al.  A Macromolecule Reversing Antibiotic Resistance Phenotype and Repurposing Drugs as Potent Antibiotics , 2020, Advanced science.

[22]  R. Schiffelers,et al.  Extracellular vesicles as drug delivery systems: Why and how? , 2020, Advanced drug delivery reviews.

[23]  Xiangliang Yang,et al.  Extracellular vesicles for tumor targeting delivery based on five features principle. , 2020, Journal of controlled release : official journal of the Controlled Release Society.

[24]  Y. Chwae,et al.  Apoptotic cell-derived exosomes: messages from dying cells , 2020, Experimental & Molecular Medicine.

[25]  M. Grumet,et al.  Trends in mesenchymal stem cell clinical trials 2004‐2018: Is efficacy optimal in a narrow dose range? , 2019, Stem cells translational medicine.

[26]  A. Gaharwar,et al.  Engineered Extracellular Vesicles with Synthetic Lipids via Membrane Fusion to Establish Efficient Gene Delivery. , 2019, International journal of pharmaceutics.

[27]  J. Wolfram,et al.  Extracellular vesicle-based drug delivery systems for cancer treatment , 2019, Theranostics.

[28]  C. Park,et al.  Drug release and kinetic models of anticancer drug (BTZ) from a pH-responsive alginate polydopamine hydrogel: Towards cancer chemotherapy. , 2019, International journal of biological macromolecules.

[29]  Hélder A Santos,et al.  Tumor exosome-based nanoparticles are efficient drug carriers for chemotherapy , 2019, Nature Communications.

[30]  J. Lötvall,et al.  Advances in therapeutic applications of extracellular vesicles , 2019, Science Translational Medicine.

[31]  I. Poon,et al.  Moving beyond size and phosphatidylserine exposure: evidence for a diversity of apoptotic cell-derived extracellular vesicles in vitro , 2019, Journal of extracellular vesicles.

[32]  Xialin Liu,et al.  A potent immunomodulatory role of exosomes derived from mesenchymal stromal cells in preventing cGVHD , 2018, Journal of Hematology & Oncology.

[33]  Sun Park,et al.  Molecular mechanisms of biogenesis of apoptotic exosome-like vesicles and their roles as damage-associated molecular patterns , 2018, Proceedings of the National Academy of Sciences.

[34]  F. Fröhlich,et al.  Rab GTPase Function in Endosome and Lysosome Biogenesis. , 2018, Trends in cell biology.

[35]  S. Shi,et al.  Circulating apoptotic bodies maintain mesenchymal stem cell homeostasis and ameliorate osteopenia via transferring multiple cellular factors , 2018, Cell Research.

[36]  D. Nam,et al.  Apoptotic Cell-Derived Extracellular Vesicles Promote Malignancy of Glioblastoma Via Intercellular Transfer of Splicing Factors. , 2018, Cancer cell.

[37]  F. Salimi,et al.  Engineered Exosomes for Targeted Transfer of siRNA to HER2 Positive Breast Cancer Cells , 2018, Applied Biochemistry and Biotechnology.

[38]  I. Poon,et al.  Apoptotic Cell-Derived Extracellular Vesicles: More Than Just Debris , 2018, Frontiers in Immunology.

[39]  J. Galipeau,et al.  Mesenchymal Stromal Cells: Clinical Challenges and Therapeutic Opportunities. , 2018, Cell stem cell.

[40]  Robert J. Ono,et al.  Injectable Coacervate Hydrogel for Delivery of Anticancer Drug-Loaded Nanoparticles in vivo. , 2018, ACS applied materials & interfaces.

[41]  T. Cai,et al.  The Fas/Fap-1/Cav-1 complex regulates IL-1RA secretion in mesenchymal stem cells to accelerate wound healing , 2018, Science Translational Medicine.

[42]  Collins Wenhan Chu,et al.  A macromolecular approach to eradicate multidrug resistant bacterial infections while mitigating drug resistance onset , 2018, Nature Communications.

[43]  C. Jorgensen,et al.  Mesenchymal stem cells-derived exosomes are more immunosuppressive than microparticles in inflammatory arthritis , 2018, Theranostics.

[44]  T. Meulia,et al.  Mesenchymal stem cell-derived extracellular vesicles attenuate influenza virus-induced acute lung injury in a pig model , 2018, Stem Cell Research & Therapy.

[45]  Dimitri Krainc,et al.  Mitochondria-lysosome contacts regulate mitochondrial fission via Rab7 GTP hydrolysis , 2018, Nature.

[46]  Graça Raposo,et al.  Shedding light on the cell biology of extracellular vesicles , 2018, Nature Reviews Molecular Cell Biology.

[47]  Yingying Zhang,et al.  Plasma membrane changes during programmed cell deaths , 2017, Cell Research.

[48]  D. Karpman,et al.  Extracellular vesicles in renal disease , 2017, Nature Reviews Nephrology.

[49]  P. Manganotti,et al.  Bortezomib-Induced Muscle Toxicity in Multiple Myeloma , 2017, Journal of neuropathology and experimental neurology.

[50]  M. Pittenger,et al.  Concise Review: MSC‐Derived Exosomes for Cell‐Free Therapy , 2017, Stem cells.

[51]  P. Kantoff,et al.  Cancer nanomedicine: progress, challenges and opportunities , 2016, Nature Reviews Cancer.

[52]  R. Schiffelers,et al.  PEGylated and targeted extracellular vesicles display enhanced cell specificity and circulation time. , 2016, Journal of controlled release : official journal of the Controlled Release Society.

[53]  S. Mathivanan,et al.  A novel mechanism of generating extracellular vesicles during apoptosis via a beads-on-a-string membrane structure , 2015, Nature Communications.

[54]  P. Moreau,et al.  Frontline therapy of multiple myeloma. , 2015, Blood.

[55]  Molly M Stevens,et al.  Active loading into extracellular vesicles significantly improves the cellular uptake and photodynamic effect of porphyrins. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[56]  J. Stow,et al.  Cytokine Secretion in Macrophages: SNAREs, Rabs, and Membrane Trafficking , 2014, Front. Immunol..

[57]  Guimei Zhang,et al.  Delivery of chemotherapeutic drugs in tumour cell-derived microparticles , 2012, Nature Communications.

[58]  György Nagy,et al.  Cellular and Molecular Life Sciences REVIEW Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles , 2022 .

[59]  J. Hedrick,et al.  Biodegradable nanostructures with selective lysis of microbial membranes. , 2011, Nature chemistry.

[60]  Andreas Bergmann,et al.  Apoptosis, Stem Cells, and Tissue Regeneration , 2010, Science Signaling.

[61]  Alejandro Sánchez Alvarado,et al.  Cell turnover and adult tissue homeostasis: from humans to planarians. , 2007, Annual review of genetics.

[62]  L. Zitvogel,et al.  Cell death modalities: classification and pathophysiological implications , 2007, Cell Death and Differentiation.

[63]  A. Dispenzieri,et al.  Synergistic activity of the proteasome inhibitor PS-341 with non-myeloablative 153-Sm-EDTMP skeletally targeted radiotherapy in an orthotopic model of multiple myeloma. , 2006, Blood.

[64]  P. Saftig,et al.  Role for Rab7 in maturation of late autophagic vacuoles , 2004, Journal of Cell Science.

[65]  E. Ségal-Bendirdjian,et al.  Staurosporine induces apoptosis through both caspase-dependent and caspase-independent mechanisms , 2001, Oncogene.

[66]  Guido Kroemer,et al.  Mitochondrio‐nuclear translocation of AIF in apoptosis and necrosis , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[67]  R. Miller,et al.  Ca2+ and Reactive Oxygen Species in Staurosporine‐Induced Neuronal Apoptosis , 1997, Journal of neurochemistry.

[68]  A. Wyllie,et al.  Apoptosis: A Basic Biological Phenomenon with Wide-ranging Implications in Tissue Kinetics , 1972, British Journal of Cancer.

[69]  Santhosh K. P. Kumar,et al.  CD45 expression by bone marrow plasma cells in multiple myeloma: clinical and biological correlations , 2005, Leukemia.