Ionizable lipid nanoparticles deliver mRNA to pancreatic β cells via macrophage-mediated gene transfer

Science Advances, Год журнала: 2023, Номер 9(4)

Опубликована: Янв. 27, 2023

Systemic messenger RNA (mRNA) delivery to organs outside the liver, spleen, and lungs remains challenging. To overcome this issue, we hypothesized that altering nanoparticle chemistry administration routes may enable mRNA-induced protein expression of reticuloendothelial system. Here, describe a strategy for delivering mRNA potently specifically pancreas using lipid nanoparticles. Our results show nanoparticles containing cationic helper lipids by intraperitoneal produces robust specific in pancreas. Most resultant occurred within insulin-producing β cells. Last, found pancreatic was dependent on horizontal gene transfer peritoneal macrophage exosome secretion, an underappreciated mechanism influences We anticipate will therapies intractable diseases such as diabetes cancer.

Язык: Английский

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Current challenges and future directions for engineering extracellular vesicles for heart, lung, blood and sleep diseases

Journal of Extracellular Vesicles, Год журнала: 2023, Номер 12(2)

Опубликована: Фев. 1, 2023

Abstract Extracellular vesicles (EVs) carry diverse bioactive components including nucleic acids, proteins, lipids and metabolites that play versatile roles in intercellular interorgan communication. The capability to modulate their stability, tissue‐specific targeting cargo render EVs as promising nanotherapeutics for treating heart, lung, blood sleep (HLBS) diseases. However, current limitations large‐scale manufacturing of therapeutic‐grade EVs, knowledge gaps EV biogenesis heterogeneity pose significant challenges clinical application diagnostics or therapeutics HLBS To address these challenges, a strategic workshop with multidisciplinary experts biology U.S. Food Drug Administration (USFDA) officials was convened by the National Heart, Lung Blood Institute. presentations discussions were focused on summarizing state science technology engineering therapeutic diseases, identifying critical regulatory suggesting potential solutions promulgate translation clinic. Benchmarks meet quality attributes set USFDA other cell‐based discussed. Development novel strategies approaches scaling‐up production control/quality analysis (QC/QA) EV‐based recognized necessary milestones future investigations.

Язык: Английский

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Extracellular Vesicles as Therapeutic Resources in the Clinical Environment

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(3), С. 2344 - 2344

Опубликована: Янв. 25, 2023

The native role of extracellular vesicles (EVs) in mediating the transfer biomolecules between cells has raised possibility to use them as therapeutic vehicles. development therapies based on EVs is now expanding rapidly; here we will describe current knowledge different key points regarding a clinical setting. These are related cell sources EVs, isolation, storage, and delivery methods, well modifications releasing for improved production EVs. Finally, depict application trials, considering impact COVID-19 pandemic these therapies, pointing out that although it promising therapy human diseases, still initial phase its patients.

Язык: Английский

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Engineered mesenchymal stem cell-derived extracellular vesicles: A state-of-the-art multifunctional weapon against Alzheimer's disease

Theranostics, Год журнала: 2023, Номер 13(4), С. 1264 - 1285

Опубликована: Янв. 1, 2023

With the increase of population aging, number Alzheimer's disease (AD) patients is also increasing.According to current estimates, approximately 11% people over 65 suffer from AD, and that percentage rises 42% among 85.However, no effective treatment capable decelerating or stopping AD progression available.Furthermore, AD-targeted drugs composed synthetic molecules pose concerns regarding biodegradation, clearance, immune response, neurotoxicity.Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are essential intercellular communication mediators holding great promise as therapeutics owing their biocompatibility, versatility, effortless storage, superior safety, ability transport messenger noncoding RNAs, proteins, lipids, DNAs, other bioactive compounds derived cells.The functionalisation engineering strategies MSC-EVs highlighted (e.g.preconditioning, drug loading, surface modification, artificial EV fabrication), which could improve by multiple therapeutic effects, including clearing abnormal protein accumulation achieving neuroprotection immunomodulatory effects.Herein, this review summarises state-of-the-art engineer MSC-EVs, discusses progress in use therapeutics, presents perspectives challenges associated with related clinical applications, concludes engineered show immense potential therapy.

Язык: Английский

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Antibody-displaying extracellular vesicles for targeted cancer therapy

Nature Biomedical Engineering, Год журнала: 2024, Номер 8(11), С. 1453 - 1468

Опубликована: Май 20, 2024

Extracellular vesicles (EVs) function as natural delivery vectors and mediators of biological signals across tissues. Here, by leveraging these functionalities, we show that EVs decorated with an antibody-binding moiety specific for the fragment crystallizable (Fc) domain can be used a modular system targeted cancer therapy. The Fc-EVs different types immunoglobulin G antibody thus to virtually any tissue interest. Following optimization engineered screening Fc-binding EV-sorting moieties, targeting cells displaying human epidermal receptor 2 or programmed-death ligand 1, well lower tumour burden extended survival mice subcutaneous melanoma tumours when systemically injected 1 loaded chemotherapeutic doxorubicin. domains may adapted display other Fc-fused proteins, bispecific antibodies antibody-drug conjugates.

Язык: Английский

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The Discovery of Extracellular Vesicles and Their Emergence as a Next-Generation Therapy

Circulation Research, Год журнала: 2024, Номер 135(1), С. 198 - 221

Опубликована: Июнь 20, 2024

From their humble discovery as cellular debris to cementing natural capacity transfer functional molecules between cells, the long-winded journey of extracellular vesicles (EVs) now stands at precipice a next-generation cell-free therapeutic tool revolutionize modern-day medicine. This perspective provides snapshot EVs emergence vibrant field biology and renaissance they usher in biomedical sciences agents for cardiovascular pathologies. Rapid development bioengineered is providing innovative opportunities overcome biological challenges such potency, cargo loading enhanced secretion, targeting circulation half-life, localized sustained delivery strategies, approaches enhance systemic circulation, uptake lysosomal escape, logistical hurdles encompassing scalability, cost, time. A multidisciplinary collaboration beyond extends chemistry, physics, biomaterials, nanotechnology, allowing rapid designer that are entering late-stage human clinical trials.

Язык: Английский

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Proteomic dissection of large extracellular vesicle surfaceome unravels interactive surface platform

Journal of Extracellular Vesicles, Год журнала: 2021, Номер 10(13)

Опубликована: Ноя. 1, 2021

Abstract The extracellular vesicle (EV) surface proteome (surfaceome) acts as a fundamental signalling gateway by bridging intra‐ and networks, dictates EVs’ capacity to communicate interact with their environment, is source of potential disease biomarkers therapeutic targets. However, our understanding protein composition large EVs (L‐EVs, 100–800 nm, mean 310 ATP5F1A, ATP5F1B, DHX9, GOT2, HSPA5, HSPD1, MDH2, STOML2), major EV‐subtype that are distinct from small (S‐EVs, 30–150 110 CD44, CD63, CD81, CD82, CD9, PDCD6IP, SDCBP, TSG101) remains limited. Using membrane impermeant derivative biotin capture proteins coupled mass spectrometry analysis, we show out 4143 identified in density‐gradient purified L‐EVs (1.07–1.11 g/mL, multiple cancer cell lines), 961 accessible. molecular diversity include (i) bona fide plasma anchored (cluster differentiation, transporters, receptors GPI implicated cell‐cell cell‐ECM interactions); (ii) surface‐associated (that released divalent ion chelator EDTA) actin cytoskeleton regulation, junction organization, glycolysis platelet activation. Ligand‐receptor analysis L‐EV surfaceome (e.g., ITGAV/ITGB1) uncovered interactome spanning 172 experimentally verified cognate binding partners ANGPTL3, PLG, VTN) highest tissue enrichment for liver. Assessment inaccessible revealed belonging COPI/II‐coated ER/Golgi‐derived vesicles mitochondria. Additionally, despite common S‐EVs, data reveals heterogeneity between the two EV‐subtype. Collectively, study provides critical insights into diverse operating at interactive platform leads future studies seeking decipher function.

Язык: Английский

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Effect of 2D and 3D Culture Microenvironments on Mesenchymal Stem Cell-Derived Extracellular Vesicles Potencies

Frontiers in Cell and Developmental Biology, Год журнала: 2022, Номер 10

Опубликована: Фев. 14, 2022

Therapeutic benefits of mesenchymal stem cells (MSCs) are now widely believed to come from their paracrine signalling, i.e. secreted factors such as cytokines, chemokines, and extracellular vesicles (EVs). Cell-free therapy using EVs is an active emerging field in regenerative medicine. Typical 2D cultures on tissue culture plastic far removed the physiological environment MSCs. The application 3D cell allows MSCs adapt cellular which, turn, influences signalling activity. In this study we evaluated impact secretion, cargo proteome composition, functional assessment immunomodulatory, anti-inflammatory anti-fibrotic properties. MSC-EVs expressed classical EV markers CD81, CD63, CD9 with particle diameter <100 nm. There were distinct changes immunomodulatory potencies where exhibited reduced indoleamine 2,3-dioxygenase (IDO) activity significantly macrophage phagocytosis. Administration following double dose bleomycin challenge aged mice showed a marked increase bodyweight loss group throughout days 7-28. Histopathological observations lung tissues increased collagen deposition, myofibroblast differentiation leukocytes infiltrations. Assessment mechanics did not improve function instead resistance damping. Proteome profiling MSC-EV composition revealed molecular enrichment (compared parental cells) differential between condition associated immune-based fibrosis/extracellular matrix/membrane organization function. This provides insight into variation protein dependent microenvironment cells, which could have implications therapeutic effect potency. Overall, work suggests that produced MSC enhance typical properties expected (immunomodulation, anti-fibrotic, anti-inflammatory). outcome highlights critical differences obtained different microenvironments, should be considered when scaling up for clinical manufacturing.

Язык: Английский

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Injectable MMP1-sensitive microspheres with spatiotemporally controlled exosome release promote neovascularized bone healing

Acta Biomaterialia, Год журнала: 2022, Номер 157, С. 321 - 336

Опубликована: Дек. 6, 2022

Bone marrow mesenchymal stromal cell-derived exosomes (BMSC-Exos) can recruit stem cells for bone repair, with neovessels serving as the main migratory channel to injury site. However, existing exosome (Exo) delivery strategies cannot reach angiogenesis phase following injury. To that end, an enzyme-sensitive Exo material responds neovessel formation during was designed in present study achieve spatiotemporally controlled release. Herein, matrix metalloproteinase-1 (MMP1) found be highly expressed neovascularized bone; a result, we proposed injectable MMP1-sensitive hydrogel microspheres (KGE) made using microfluidic chip prepared by mixing self-assembling peptide (KLDL-MMP1), GelMA, and BMSC-Exos. The results revealed KGE had uniform diameter of 50-70 µm, ideal minimally invasive injection could release response MMP1 expression. In vitro experiments demonstrated less cytotoxicity promote migration osteodifferentiation BMSCs. Furthermore, vivo confirmed repair recruiting CD90+ via neovessels. Collectively, our suggest enzyme-responsive promising Exo-secreting accelerating healing. STATEMENT OF SIGNIFICANCE: Exosomes spread through blood vessels activate participate but under normal circumstances, lacking sustained-release materials maintained until phase. this study, bone, then microsphere carries temporally spatially neovascularization, which maximizes ability cells. Different from previous focus on promoting accelerate healing, is brand new strategy stimuli-responsive formation. addition, preparation self-assembled also first time.

Язык: Английский

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Extracellular vesicles as next generation immunotherapeutics

Seminars in Cancer Biology, Год журнала: 2023, Номер 90, С. 73 - 100

Опубликована: Фев. 10, 2023

Язык: Английский

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