RNA splicing as a biomarker and phenotypic driver of meningioma DNA methylation groups.

BACKGROUND: Advances in our understanding of the molecular biology of meningiomas have led to significant gains in the ability to predict patient prognosis and tumor recurrence and to identify novel targets for therapeutic design. Specifically, classification of meningiomas based on DNA methylation has greatly improved our ability to risk stratify patients, however new questions have arisen in terms of the underlying impact these DNA methylation signatures have on meningioma biology. METHODS: This study utilizes RNA-seq data from 486 meningioma samples corresponding to three meningioma DNA methylation groups (Merlin-intact, Immune-enriched, and Hypermitotic), followed by in vitro experiments utilizing human meningioma cell lines. RESULTS: We identify alterations in RNA splicing between meningioma DNA methylation groups including individual splicing events that correlate with Hypermitotic meningiomas and predict tumor recurrence and overall patient prognosis and compile a set of splicing events that can accurately predict DNA methylation classification based on RNA-seq data. Furthermore, we validate these events using RT-PCR in patient samples and meningioma cell lines. Additionally, we identify alterations in RNA binding proteins and splicing factors that lie upstream of RNA splicing events, including upregulation of SRSF1 in Hypermitotic meningiomas which we show drives alternative RNA splicing changes. Finally, we design splice switching antisense oligonucleotides to target RNA splicing changes in NASP and MFF observed in Hypermitotic meningiomas, providing a rationale for RNA-based therapeutic design. CONCLUSIONS: RNA splicing is an important driver of meningioma phenotypes that can be useful in prognosticating patients and as a potential exploit for therapeutic vulnerabilities.

recAP administration ameliorates sepsis outcomes through modulation of gut and liver inflammation.

Sepsis, broadly described as a systemic infection, is one of the leading causes of death and long-term disability worldwide. There are limited therapeutic options available that either improve survival and/or improve the quality of life in survivors. Ilofotase alfa, also known as recombinant alkaline phosphatase (recAP), has been associated with reduced mortality in a subset of patients with sepsis-associated acute kidney injury. However, whether recAP exhibits any therapeutic benefits in other organ systems beyond the kidney is less clear. The objective of this study was to evaluate the effects of recAP on survival, behavior, and intestinal inflammation in a mouse model of sepsis, cecal ligation and puncture (CLP). Following CLP, either recAP or saline vehicle was administered via daily intraperitoneal injections to determine its treatment efficacy from early through late sepsis. We found that administration of recAP suppressed indices of inflammation in the gut and liver but did not improve survival or behavioral outcomes. These results demonstrate that recAP's therapeutic efficacy in the gut and liver may provide a valuable treatment to improve long-term outcomes in sepsis survivors.

Extracellular vesicles transport RNA between cells: Unraveling their dual role in diagnostics and therapeutics.

Modern methods of molecular diagnostics and therapy have revolutionized the field of medicine in recent years by providing more precise and effective tools for detecting and treating diseases. This progress includes a growing exploration of the body's secreted vesicles, known as extracellular vesicles (EVs), for both diagnostic and therapeutic purposes. EVs are a heterogeneous population of lipid bilayer vesicles secreted by almost every cell type studied so far. They are detected in body fluids and conditioned culture media from living cells. EVs play a crucial role in communication between cells and organs, both locally and over long distances. They are recognized for their ability to transport endogenous RNA and proteins between cells, including messenger RNA (mRNA), microRNA (miRNA), misfolded neurodegenerative proteins, and several other biomolecules. This review explores the dual utilization of EVs, serving not only for diagnostic purposes but also as a platform for delivering therapeutic molecules to cells and tissues. Through an exploration of their composition, biogenesis, and selective cargo packaging, we elucidate the intricate mechanisms behind RNA transport between cells via EVs, highlighting their potential use for both diagnostic and therapeutic applications. Finally, it addresses challenges and outlines prospective directions for the clinical utilization of EVs.

Systemic Brain Delivery of Oligonucleotide Therapeutics Enhanced by Protein Corona-Assisted DNA Cubes.

The systemic delivery of oligonucleotide therapeutics to the brain is challenging but highly desirable for the treatment of brain diseases undruggable with traditional small-molecule drugs. In this study, a set of DNA nanostructures is prepared and screened them to develop a protein corona-assisted platform for the brain delivery of oligonucleotide therapeutics. The biodistribution analysis of intravenously injected DNA nanostructures reveals that a cube-shaped DNA nanostructure (D-Cb) can penetrate the brain-blood barrier (BBB) and reach the brain tissue. The brain distribution level of D-Cb is comparable to that of other previous nanoparticles conjugated with brain-targeting ligands. Proteomic analysis of the protein corona formed on D-Cb suggests that its brain distribution is driven by endothelial receptor-targeting ligands in the protein corona, which mediate transcytosis for crossing the BBB. D-Cb is subsequently used to deliver an antisense oligonucleotide (ASO) to treat glioblastoma multiforme (GBM) in mice. While free ASO is unable to reach the brain, ASO loaded onto D-Cb is delivered efficiently to the brain tumor region, where it downregulates the target gene and exerts an anti-tumor effect on GBM. D-Cb is expected to serve as a viable platform based on protein corona formation for systemic brain delivery of oligonucleotide therapeutics.

The Interplay Between Health Disparities and Acceptability of Virtual Reality: A Survey Study.

Virtual reality (VR) has emerged as a nonpharmacological adjuvant to manage acute and chronic pain symptoms. The goal of this survey study was to determine the acceptability of VR among chronic pain participants hailing from distressed and prosperous neighborhoods in the state of Maryland. We hypothesized that pain severity and interference vary in groups experiencing health disparities, potentially influencing VR's acceptability. From March 11 to March 15, 2020, we surveyed a cohort of clinically phenotyped participants suffering from chronic orofacial pain. Participants were asked to express their willingness to participate in a longitudinal VR study and their expectation of pain relief from using VR. Seventy out of 350 participants with chronic pain completed the survey (response rate: 20%). There was no difference in the likelihood of responding to the survey based on their neighborhood distress. Among survey respondents and nonrespondents, similar proportions of participants were from distressed neighborhoods. Among the respondents, 63 (90%) and 59 (84.3%) were willing to participate and expected to experience pain relief from the VR intervention, respectively. Age, sex, race, neighborhood distress, severity of pain, and prior VR experience did not influence willingness to participate in the VR trial or the expectations of VR-induced improvement. These findings suggest that VR as an adjuvant intervention is potentially accepted by chronic pain participants, irrespective of neighborhood-level social determinants of health.

A systematic review of non-coding RNA therapeutics in early clinical trials: a new perspective against cancer.

Targeting non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), has recently emerged as a promising strategy for treating malignancies and other diseases. In recent years, the development of ncRNA-based therapeutics for targeting protein-coding and non-coding genes has also gained momentum. This review systematically examines ongoing and completed clinical trials to provide a comprehensive overview of the emerging landscape of ncRNA-based therapeutics. Significant efforts have been made to advance ncRNA therapeutics to early clinical studies. The most advanced trials have been conducted with small interfering RNAs (siRNAs), miRNA replacement using nanovector-entrapped miRNA mimics, or miRNA silencing by antisense oligonucleotides. While siRNA-based therapeutics have already received FDA approval, miRNA mimics, inhibitors, and lncRNA-based therapeutics are still under evaluation in preclinical and early clinical studies. We critically discuss the rationale and methodologies of ncRNA targeting strategies to illustrate this rapidly evolving field.

Treatment Patterns and Preferences for Graves' Disease in Korea: Insights from a Nationwide Cohort Study.

Treatment patterns and preferences for patients with Graves' disease (GD) vary across countries. In this study, we assessed the initial therapies and subsequent treatment modalities employed for GD in real-world clinical practice in Korea. We analyzed 452,001 patients with GD from 2004 to 2020, obtained from the Korean National Health Insurance Service database. Initial treatments included antithyroid drug (ATD) therapy (98% of cases), thyroidectomy (1.3%), and radioactive iodine (RAI) therapy (0.7%). The rates of initial treatment failure were 58.5% for ATDs, 21.3% for RAI, and 2.1% for thyroidectomy. Even among cases of ATD treatment failure or recurrence, the rates of RAI therapy remained low. Regarding initial treatment, the 5-year remission rate was 46.8% among patients administered ATDs versus 91.0% among recipients of RAI therapy; at 10 years, these rates were 59.2% and 94.0%, respectively. Our findings highlight a marked disparity in the use of RAI therapy in Korea compared to Western countries. Further research is required to understand the reasons for these differences in treatment patterns.

The complement model disease paroxysmal nocturnal hemoglobinuria.

We describe initial, current, and future aspects of complement activation and inhibition in the rare hematological disease paroxysmal nocturnal hemoglobinuria (PNH). PNH is a rare but severe hematological disorder characterized by complement-mediated intravascular hemolysis resulting in anemia and severe thrombosis. Insights into the complement-mediated pathophysiology ultimately led to regulatory approval of the first-in-class complement inhibitor, eculizumab, in 2007. This anti-complement C5 therapy resulted in the stabilization of many hematologic parameters and dramatically reduced the often fatal, coagulant-resistant thrombotic events. Despite the remarkable clinical success, a substantial proportion of PNH patients experience suboptimal clinical responses during anti-C5 therapy. We describe the identification and mechanistic dissection of four unexpected processes responsible for such suboptimal clinical responses: (1) pharmacokinetic and (2) pharmacodynamic intravascular breakthrough hemolysis, (3) continuing low-level residual intravascular hemolysis, and (4) extravascular hemolysis. Novel complement therapeutics mainly targeting different complement proteins proximal in the cascade attempt to address these remaining problems. With five approved complement inhibitors in the clinic and many more being evaluated in clinical trials, PNH remains one of the complement diseases with the highest intensity of clinical research. Mechanistically unexpected breakthrough events occur not only with C5 inhibitors but also with proximal pathway inhibitors, which require further mechanistic elaboration.

Comprehensive analysis, diagnosis, prognosis, and cordycepin (CD) regulations for GSDME expressions in pan-cancers.

The Gasdermin E gene (GSDME) plays roles in deafness and cancers. However, the roles and mechanisms in cancers are complex, and the same gene exhibits different mechanisms and actions in different types of cancers. Online databases, such as GEPIA2, cBioPortal, and DNMIVD, were used to comprehensively analyze GSDME profiles, DNA methylations, mutations, diagnosis, and prognosis in patients with tumor tissues and matched healthy tissues. Western blotting and RT-PCR were used to monitor the regulation of GSDME by Cordycepin (CD) in cancer cell lines. We revealed that GSDME expression is significantly upregulated in eight cancers (ACC, DLBC, GBM, HNSC, LGG, PAAD, SKCM, and THYM) and significantly downregulated in seven cancers (COAD, KICH, LAML, OV, READ, UCES, and UCS). The overall survival was longer only in ACC, but shorter in four cancers, including COAD, KIRC, LIHC, and STAD, when GSDME was highly expressed in cancers compared with the corresponding normal tissues. Moreover, the high expression of GSDME was negatively correlated with the poor prognosis of ACC, while the low expression of GSDME was negatively correlated with the poor prognosis of COAD, suggesting that GSDME might serve as a good prognostic factor in these two cancer types. Accordingly, results indicated that the DNA methylations of those 7 CpG sites constitute a potentially effective signature to distinguish different tumors from adjacent healthy tissues. Gene mutations for GSDME were frequently observed in a variety of tumors, with UCES having the highest frequency. Moreover, CD treatment inhibited GSDME expression in different cancer cell lines, while overexpression of GSDME promoted cell migration and invasion. Thus, we have systematically and successfully clarified the GSDME expression profiles, diagnostic values, and prognostic values in pan-cancers. Targeting GSDME with CD implies therapeutic significance and a mechanism for antitumor roles in some types of cancers via increasing the sensitivity of chemotherapy. Altogether, our study may provide a strategy and biomarker for clinical diagnosis, prognostics, and treatment of cancers by targeting GSDME.

Current status and future prospects of Chinese mobile apps for hypertension management.

OBJECTIVE: This study aimed to evaluate the current situation of Chinese mobile apps for hypertension management and explore patients' real requirements for app use, providing a theoretical basis for the future improvement of hypertension apps. METHODS: We reviewed hypertension management apps from mobile app platforms, and summarized their functional characteristics. In addition, we conducted an online survey among 1000 hypertensive patients, collected valid responses, and analyzed the feedback data. RESULTS: Forty hypertension management apps were analyzed, with 72.5% offering no more than six functions, indicating limited coverage of advanced and comprehensive functionalities. Among the 934 valid survey responses, patients emphasized four main functions in apps for hypertension management: long-term dynamic blood pressure monitoring, scientific lifestyle management, strict medication management and systematic health knowledge delivering. CONCLUSION: The existing hypertension management apps mainly serve as "Digital Health" tools with unclear clinical efficacy. The future development of these apps lies in how they transition to "Digital Therapeutics" solutions to better meet patients' needs and provide clear clinical advantages.

Semaxanib, a VEGF inhibitor, suppresses melanogenesis by modulating CRTC3 independently of VEGF signaling.

BACKGROUND: Dysregulation of melanogenesis contributes to the development of skin hyperpigmentation diseases, which poses a treatment challenge. Following the establishment of CRTC3 screening methods to explore small molecules inhibiting melanogenesis for the topical treatment of hyperpigmentation diseases, we identified a candidate molecule, semaxanib. OBJECTIVE: To explore the antimelanogenic effects of semaxanib, a vascular endothelial growth factor receptor (VEGFR) 2 inhibitor, for potential applications in hyperpigmentation management and to unravel the role of VEGF signaling in melanocyte biology by investigating mechanism of action of semaxanib. METHODS: Mouse-derived spontaneously immortalized melanocytes, B16F10, and normal human primary epidermal melanocytes cells were treated with semaxanib, and cellular responses were assessed using cell viability assays and melanin content measurements. Molecular mechanisms were investigated using transcriptional activity assays, reverse-transcription polymerase chain reaction, and immunoblotting analysis. In vivo studies were conducted using an epidermis-humanized transgenic mouse model and ex vivo human skin tissues. RESULTS: Semaxanib ameliorated melanin content in cultured melanocytes by downregulating the expression of melanogenesis-associated genes by suppressing the CRTC3/microphthalmia-associated transcription factors. Topical application of semaxanib reduced melanin accumulation in the ultraviolet B-stimulated ex vivo human epidermis and tail of K14-stem cell factor transgenic mice. Mechanistically, the antimelanogenic effect induced by semaxanib was associated with SIK2-CRTC3-MITF rather than VEGF signaling in melanocytes. CONCLUSION: Semaxanib emerges as a promising candidate for the development of therapeutics for hyperpigmentation, potentially working independently of VEGF signaling in human melanocytes.

The relationship between treatment-related changes in total hip bone mineral density measured after 12, 18 and 24 months and fracture risk reduction in osteoporosis clinical trials: the FNIH-ASBMR-SABRE Project.

There is a strong association between total hip bone mineral density (THBMD) changes after 24 months of treatment and reduced fracture risk. We examined whether changes in THBMD after 12- and 18 months of treatment are also associated with fracture risk reduction. We used individual patient data (n = 122 235 participants) from 22 randomised, placebo-controlled, double-blind trials of osteoporosis medications. We calculated the difference in mean percent change in THBMD (active-placebo) at 12, 18, and 24 months using data available for each trial. We determined the treatment-related fracture reductions for the entire follow-up period, using logistic regression for radiologic vertebral fractures and Cox regression for hip, non-vertebral, "all" (combination of non-vertebral, clinical vertebral, and radiologic vertebral) fractures, and all clinical fractures (combination of non-vertebral and clinical vertebral). We performed meta-regression to estimate the study-level association (r2 and 95% confidence interval) between treatment-related differences in THBMD changes for each BMD measurement interval and fracture risk reduction. The meta-regression revealed that for vertebral fractures, the r2 (95% confidence interval) was 0.59 (0.19, 0.75), 0.69 (0.32, 0.82), and 0.73 (0.33, 0.84) for 12, 18 and 24 months, respectively. Similar patterns were observed for hip: r2 = 0.27 (0.00, 0.54), 0.39 (0.02, 0.63), and 0.41 (0.02, 0.65); non-vertebral: r2 = 0.27 (0.01, 0.52), 0.49 (0.10, 0.69), and 0.53 (0.11, 0.72); all fractures: r2 = 0.44 (0.10, 0.64), 0.63 (0.24, 0.77), and 0.66 (0.25, 0.80); and all clinical fractures: r2 = 0.46 (0.11, 0.65), 0.64 (0.26, 0.78), and 0.71 (0.32, 0.83), for 12-, 18- and 24-month changes in THBMD, respectively. These findings demonstrate that treatment-related THBMD changes at 12, 18 and 24 months are associated with fracture risk reductions across trials. We conclude that BMD measurement intervals as short as 12 months could be used to assess fracture efficacy, but the association is stronger with longer BMD measurement intervals.

In this study, we looked at how changes in hip bone density over time relate to the risk of fractures in people taking osteoporosis medications. We analysed data from over 122 000 participants across 22 different clinical trials. We found that the increase in bone density measured after 12, 18, and 24 months of treatment was linked to the risk of fractures. Specifically, greater improvements in bone density were associated with fewer fractures in the spine, hips, and other bones. Using statistical methods, we calculated the strength of this association. We discovered that the later we measured bone mineral density in people taking the medication, the stronger the link between improved bone density and reduced fracture risk became. Our findings suggest that bone density measurements after 12 months of treatment could help predict how well a medication will prevent fractures. However, the best predictions came from bone density changes measured over longer periods.

Critical Insights from Recent Outbreaks of Mycoplasma pneumoniae: Decoding the Challenges and Effective Interventions Strategies.

Mycoplasma pneumoniae (M. pneumoniae) continues to pose a significant disease burden on global public health as a respiratory pathogen. The antimicrobial resistance among M. pneumoniae strains has complicated the outbreak control efforts, emphasizing the need for robust surveillance systems and effective antimicrobial stewardship programs. This review comprehensively investigates studies stemming from previous outbreaks to emphasize the multifaceted nature of M. pneumoniae infections, encompassing epidemiological dynamics, diagnostic innovations, antibiotic resistance, and therapeutic challenges. We explored the spectrum of clinical manifestations associated with M. pneumoniae infections, emphasizing the continuum of disease severity and the challenges in gradating it accurately. Artificial Intelligence and Machine Learning have emerged as promising tools in M. pneumoniae diagnostics, offering enhanced accuracy and efficiency in identifying infections. However, their integration into clinical practice presents hurdles that need to be addressed. Further, we elucidate the pivotal role of pharmacological interventions in controlling and treating M. pneumoniae infections as the efficacy of existing therapies is jeopardized by evolving resistance mechanisms. Lessons learned from previous outbreaks underscore the importance of adaptive treatment strategies and proactive management approaches. Addressing these complexities demands a holistic approach integrating advanced technologies, genomic surveillance, and adaptive clinical strategies to effectively combat this pathogen.

A glimpse into the hidden world of the flexible C-terminal protein binding domains of human RAD52.

Human RAD52 protein binds DNA and is involved in genomic stability maintenance and several forms of DNA repair, including homologous recombination and single-strand annealing. Despite its importance, there are very few structural details about the variability of the RAD52 ring size and the RAD52 C-terminal protein-protein interaction domains. Even recent attempts to employ cryogenic electron microscopy (cryoEM) methods on full-length yeast and human RAD52 do not reveal interpretable structures for the C-terminal half that contains the replication protein A (RPA) and RAD51 binding domains. In this study, we employed the monodisperse purification of two RAD52 deletion constructs and small angle X-ray scattering (SAXS) to construct a structural model that includes RAD52's RPA binding domain. This model is of interest to DNA repair specialists as well as for drug development against HR-deficient cancers.

SLFN11 and ATR as targets for overcoming cisplatin resistance in ovarian cancer cells.

The levels and activities of the DNA/RNA helicase schlafen11 (SLFN11) and the serine/threonine-protein kinase ataxia telangiectasia and Rad3-related protein (ATR) may determine cancer cell sensitivity to DNA damaging agents, including platinum drugs. Here, we studied the roles of SLFN11 and ATR in cisplatin resistance of ovarian cancer using cell lines displaying acquired or intrinsic cisplatin resistance. W1CR, the cisplatin-resistant subline of W1 ovarian cancer cells, displayed reduced SLFN11 levels. HDAC inhibition using entinostat returned an epigenetic downregulation of SLFN11 in W1CR cells, caused SLFN11 re-expression and re-sensitized these cells to cisplatin. Moreover, entinostat also sensitized intrinsically resistant EFO21 ovarian cancer cells to cisplatin by upregulating SLFN11. However, SLFN11 was not involved in cisplatin resistance in all other cell models. Thus, SLFN11 expression is not a general cisplatin resistance marker in ovarian cancer. In contrast, inhibition of the DNA damage repair master regulator ATR using sub-toxic concentrations of elimusertib sensitized parental cell lines as well as intrinsically resistant EFO21 cells to cisplatin, and fully reversed acquired cisplatin resistance in cisplatin-adapted sublines W1CR, A2780cis, and KuramochirCDDP2000. Mechanisms underlying ATR-mediated cisplatin resistance differed between the cell lines and included CHK1/WEE1 signaling and induction of homologous recombination. In conclusion, SLFN11 and ATR are involved in ovarian cancer cisplatin resistance. Although our data identify ATR as key target for tackling cisplatin resistance in ovarian cancer, future studies are needed to identify biomarkers that indicate, which individual ovarian cancers benefit from SLFN11 re-activation and/or ATR inhibition.

Recent developments in cancer diagnosis and treatment using nanotechnology.

The article provides an insightful overview of the pivotal role of nanotechnology in revolutionizing cancer diagnosis and treatment. It discusses the critical importance of nanoparticles in enhancing the accuracy of cancer detection through improved imaging contrast agents and the synthesis of various nanomaterials designed for oncology applications. The review broadly classifies nanoparticles used in therapeutics, including metallic, magnetic, polymeric, and many other types, with an emphasis on their functions in drug delivery systems for targeted cancer therapy. It details targeting mechanisms, including passive and intentional targeting, to maximize treatment efficacy while minimizing side effects. Furthermore, the article addresses the clinical applications of nanomaterials in cancer treatment, highlights prospects, and addresses the challenges of integrating nanotechnology into cancer treatment.

Delivery vehicle and route of administration influences self-amplifying RNA biodistribution, expression kinetics, and reactogenicity.

Self-amplifying RNA (saRNA) is a next-generation RNA platform derived from an alphavirus that enables replication in host cytosol, offering a promising shift from traditional messenger RNA (mRNA) therapies by enabling sustained protein production from minimal dosages. The approval of saRNA-based vaccines, such as the ARCT-154 for COVID-19 in Japan, underscores its potential for diverse therapeutic applications, including vaccine development, cancer immunotherapy, and gene therapy. This study investigates the role of delivery vehicle and administration route on saRNA expression kinetics and reactogenicity. Employing ionizable lipid-based nanoparticles (LNPs) and polymeric nanoparticles, we administered saRNA encoding firefly luciferase to BALB/c mice through six routes (intramuscular (IM), intradermal (ID), intraperitoneal (IP), intranasal (IN), intravenous (IV), and subcutaneous (SC)), and observed persistent saRNA expression over a month. Our findings reveal that while LNPs enable broad route applicability and stability, pABOL (poly (cystamine bisacrylamide-co-4-amino-1-butanol)) formulations significantly amplify protein expression via intramuscular delivery. Notably, the disparity between RNA biodistribution and protein expression highlight the nuanced interplay between administration routes, delivery vehicles, and therapeutic outcomes. Additionally, our research unveiled distinct biodistribution profiles and inflammatory responses contingent upon the chosen delivery formulation and route. This research illuminates the intricate dynamics governing saRNA delivery, biodistribution and reactogenicity, offering essential insights for optimizing therapeutic strategies and advancing the clinical and commercial viability of saRNA technologies.

Trends in Developing Extracellular Vesicle-Based Therapeutics.

Extracellular vesicles are nano-sized vesicles surrounded by lipid bilayers, and all cells release them to the extracellular environment for communication. Extracellular vesicles consist of molecules with various biological activities and can play essential roles as therapeutics, so they attract much attention as next-generation modalities to treat various diseases. As extracellular vesicles are cell-derived nanovesicles, they are favorable to be developed as therapeutics, but they also have limitations. In addition, there are a number of things to consider in terms of manufacturing, quality control, non-clinical studies, and clinical trials during the development of extracellular vesicle-based therapeutics. Meanwhile, as much attention has been paid to the potentials of extracellular vesicles as therapeutics, many biopharmaceutical companies are trying to develop extracellular vesicle-based therapeutics. This review will introduce the advantages and limitations of extracellular vesicles as therapeutics. In addition, it will cover things to consider during developing extracellular vesicle-based therapeutics and development cases of extracellular vesicle-based therapeutics.