Mesenchymal stem cells (MSCs) have significant potential in regenerative medicine due to their multipotency, however, they face clinical challenges such as limited expansion and heterogeneity. Induced pluripotent stem cell-derived MSCs (iMSCs) are promising alternatives. The present study compared the effects of exosomes from bone marrow stromal MSCs (BMSCs) and iMSCs on A549 and MCF7 cancer cells to explore the unique properties of iMSCs. Proliferation assays revealed that both exosome types inhibited MCF7 and A549 cell proliferation at 24 h (P≤0.0001 for both) compared with the control, with BMSC-exosomes (Exos) exerting a more significant effect on MCF7 cells (P≤0.01). After 48 h, the significant effects of the BMSC-Exos were no longer observed on either cell line, whereas the iMSC-Exos continued to suppress A549 cell proliferation (P≤0.001 compared with the control; P≤0.01 compared with BMSC-Exos), indicating a longer-lasting effect. An investigation of senescence-associated β-galactosidase (SA-βGal) activity revealed no significant effect on senescence induction in MCF7 cells treated with either type of exosomes. By contrast, compared with the control treatment, the treatment of A549 cells with exosomes resulted in a significant increase in the number of senescent cells (P≤0.0001). While the apoptosis assay performed by flow cytometry revealed no significant effect on apoptosis, this increase in senescence aligned with the decreased proliferation observed in A549 cells, indicating that the antitumor effect of the exosomes on A549 cells was mediated partially through the induction of senescence. Wound healing assays revealed that BMSC-Exos significantly increased the migration of MCF7 cells at 20 h (P≤0.01). However, this effect was reversed at 47 h (P≤0.05), indicating a time-dependent effect of BMSC-Exos. In A549 cells, no significant difference in migration was observed after treatment with either exosome preparation. These findings highlight the distinct effects of iMSC- and BMSC-derived exosomes on cancer cells, emphasizing the need for further investigations into their therapeutic potential and underlying mechanisms.

Pancreatic cancer (PC) is a highly lethal and aggressive malignancy, currently one of the leading causes of cancer-related deaths worldwide, in both women and men. PC is highly resistant to standard chemotherapy (CT) because its immunosuppressive and hypoxic tumor microenvironment and a dense desmoplastic stroma compartment extensively limit drug accessibility and perfusion. Although CT is one of the main therapeutic strategies for PC management contributing to tumor eradication through a cytotoxic effect, CT is associated with a poor pharmacokinetic profile and provokes deleterious systemic toxicity. This low efficacy-poor safety scenario urgently calls for innovative and highly specific therapeutic strategies to counteract this urgent clinical challenge. Nanotechnology-based precision materials for cancer may help improve drug stability and minimize the systemic cytotoxic effects by increasing drug tumor accumulation and also enabling controlled release, but several drawbacks still persist, such as the poor targeting efficiency. In the last few years increased attention has been paid to bioinspired nanosystems that can mimic either partially or totally biological systems, including lipid layers as suitable stealth coatings resembling the composition of cell membranes, lipoprotein- and blood protein-based nanosystems, and cell membrane-derived systems, such as extracellular vesicles, cell membrane nanovesicles and cell membrane-coated nanosystems, which display intrinsic cancer-targeting abilities, enhanced biocompatibility, decreased immunogenicity, and prolonged blood circulation profile. This review covers the recent breakthroughs on advanced biomimetic PC-targeted nanosystems, focusing on their design, properties and applications as innovative, multifunctional and versatile tools paving the way to improved PC diagnosis and treatment.

In recent years, the significant role of anticancer drugs in cancer treatment has garnered considerable attention. However, the application of these drugs is largely limited by their short half-life in blood circulation, low cellular uptake efficiency, and off-target effects. Exosomes, which serve as crucial messengers in intercellular communication, exhibit unique advantages in molecular delivery compared to traditional synthetic carriers, thereby offering new possibilities for modern drug delivery systems. Exosomes possess organotropic functions and are naturally produced by cells, making them promising candidates for natural drug delivery systems with organotropic properties and minimal side effects. These naturally derived carriers can achieve stable, efficient, and selective delivery of anticancer drugs, thereby enhancing the efficacy and potential of anticancer agents in cancer immunotherapy. This review provides a concise overview of the unique characteristics of exosomes related to anticancer drug delivery, strategies for utilizing exosomes as carriers in cancer therapy, and the latest advancements in the field.

Digestive system tumors constitute a major subset of malignancies, consistently ranking among the leading causes of mortality globally. Despite limitations inherent in current therapeutic modalities, recent advancements in targeted therapy and drug delivery systems have led to significant improvements in the efficacy of pharmacotherapy for digestive system tumors. In this context, exosomes - naturally occurring nanoscale vesicles - have emerged as promising drug delivery candidates due to their intrinsic molecular transport capabilities, superior biocompatibility, and targeted recognition of tumor cells. The integration of exosomes into cancer therapeutics represents a novel and potentially transformative approach for treating digestive system tumors, which may drive further progress in this field. This review comprehensively examines the sources, loading mechanisms, and therapeutic efficacy of exosomes in the context of digestive system tumor treatment. Furthermore, it discusses the opportunities and challenges associated with exosomes, offering insights into their future role within the therapeutic armamentarium against digestive tumors.

Mesenchymal stem cells (MSCs) are currently being used in clinical trials for the treatment of a wide range of diseases and have a wide range of applications in the fields of tissue engineering and regeneration. Exosomes are extracellular vesicles containing a variety of components such as proteins, nucleic acids and lipids, which are widely present in biological fluids and have the functions of participating in intercellular information transfer, immune response and tissue repair, and can also be used as carriers to target and deliver tumors to improve therapeutic effects. Mesenchymal stem cell-derived Exosomes (MSC-Exos), which have the advantages of low immunogenicity and high tumor homing ability, have attracted much attention in targeted drug delivery. Here, we review the current knowledge on the involvement of MSC-Exos in tumor progression and their potential as drug delivery systems in targeted therapies. It also discusses the advantages and prospects of MSC-Exos as a drug carrier and the challenges that still need to be overcome.

The effective treatment of Alzheimer's disease (AD) is challenging because of its complex and controversial pathological mechanisms. Moreover, multiple barriers, such as the blood-brain barrier (BBB), reduce drug delivery efficiency. Microglia-related neuroinflammation has recently attracted increasing attention as a possible cause of AD and has become a novel therapeutic target. Therefore, overcoming the BBB and targeted delivery of anti-inflammatory agents to microglia seem to be effective practical strategies for treating AD. A large proportion of natural active extracts possess exceptional immunomodulating capabilities. In this study, the cooperative delivery of berberine (Ber) and palmatine (Pal) by transferrin-decorated extracellular vesicles (Tf-hEVs-Ber/Pal), which can cross the BBB and precisely target microglia, was performed. This nanosystem effectively cleared amyloid β-protein (Aβ) aggregates, significantly regulated the neuroinflammatory environment both in vitro and in vivo and markedly altered the behavior and improved the cognitive and learning abilities of AD model mice. The efficacy of a microglia-targeting combined therapeutic approach for AD was demonstrated, which broadens the potential application of Chinese herbal ingredients.

Diabetic cataract (DC) represents a highly prevalent ocular manifestation resulting from diabetes often culminating in vision impairment among individuals with diabetes. Regrettably, the armamentarium of pharmaceutical interventions capable of both delaying and thwarting the onset of DC remains conspicuously sparse. Based on contemporary investigations, the pathogenesis of DC is prominently influenced by oxidative harm to the crystalline lens and the nonenzymatic glycosylation of lens proteins. Consequently, we have developed self-regenerating cerium oxide nanoparticles (CeO2 NPs), enveloped with resveratrol (RSV) and exosomal-microRNA (miRNA) to alleviate the effects of DC in an in vitro model. Moreover, the inclusion of RSV within CeO2 NPs serves a dual purpose. It can act as an antioxidant, minimizing glycation, and induce oxidative stress by effectively neutralizing reactive oxygen species (ROS). Additionally, it serves as a glycation inhibitor effectively preventing the cross-linking. Consequently, it helps minimize the glucose level in hemoglobin and inhibits the formation of advanced glycation end products (AGEs). Likewise, the CeO2-exosomal-miRNA when treated alone found to slightly impede the viability of human lens epithelial cells (HLEC) and induce apoptosis by suppressing the expression of α-crystalline gene (CRYAA). Particularly, miRNAs target genes associated with oxidative stress pathways, protein glycation, and the generation of AGEs, hence preventing structural damage to lens proteins. Compared with CeO2, RSV-CeO2, and miRNA-RSV-CeO2, the presence of miRNA-RSV-CeO2 led to a significant decrease in hemoglobin glycation. Remarkably, miRNA-RSV-CeO2 NPs attenuate the formation of malondialdehyde (MDA) and conjugated dienes (CD) with a relative value of 14.63 and 11.37 nmol/mg. As per the report, this method presents a promising opportunity to implement the proposed material combination for attenuating diabetic cataracts.

The pancreas is made of two compartments: the exocrine pancreas, a source of digestive enzymes, and the endocrine islets which produce vital hormones. Distinct diseases could arise in the pancreas such as diabetes, neuroendocrine tumors, pancreatitis, and pancreatic cancers. Various treatment methods are being researched against these diseases. Treatment with recombinant proteins, therapeutic antibodies, vaccination, gene therapy, tissue engineering, and stem cell treatment are treatment methods. Furthermore, biomarkers are important for both treatment and diagnosis. However, some of the treatment methods mentioned above have not yet been applied to some pancreatic diseases. This review provides insights into the latest advancements in diagnosis and treatment for pancreatic diseases within the scope of medical biotechnology. In addition, some methods that are not yet used for treatment purposes for pancreatic diseases but are used in other diseases that occur in different organs due to similar reasons have been investigated. In this context, possible diagnosis and treatment methods for pancreatic diseases are interpreted. The first aim of this review is to bring together and present the current diagnosis and treatment methods for pancreatic diseases. The second aim is to highlight methods that may have treatment potential by comparing pancreatic diseases that cannot be treated with similar diseases.

Extracellular vesicles (EVs) have emerged as promising bioactive carriers for delivering therapeutic agents, including nucleic acids, proteins, and small-molecule drugs, owing to their excellent physicochemical stability and biocompatibility. However, comprehensive reviews on the various types of EV-based nanomedicines for cancer therapy remain scarce. This review explores the potential of EVs as antitumor nanomedicines. Methods for EV extraction, drug loading, and engineering modifications are systematically examined, and the strengths and limitations of these technical approaches are critically assessed. Additionally, key strategies for developing EV-based antitumor therapies are highlighted. Finally, the opportunities and challenges associated with advancing EVs toward clinical translation are discussed. With the integration of multiple disciplines, robust EV-based therapeutic platforms are expected to be manufactured to provide more personalized and effective solutions for oncology patients.

Interest in prostate cancer as a research topic has gradually increased. As a result, a series of innovative treatment strategies have emerged with an in-depth understanding of the disease. Owing to their unique biological characteristics, mesenchymal stromal cell exosomes (MSC-Exos) have garnered significant attention for their potential to deliver targeted drugs and enable precise prostate cancer treatment. Herein, prostate cancer treatment with MSC-Exos drug-delivery systems is reviewed. This review provides a comprehensive introduction to the advantages of these systems, current research trends and progress, as well as an analysis of current challenges and future research directions. Moreover, this review lays a solid foundation for the continued development and application of MSC-Exos.

Extracellular vesicles (EVs) are key mediators in the communication between cancer cells and their microenvironment, significantly influencing drug resistance. This review provides a comprehensive analysis of the roles of EVs in promoting drug resistance through mechanisms such as drug efflux, apoptosis resistance, autophagy imbalance, and tumor microenvironment modulation. Despite extensive research, details of EVs biogenesis, cargo selection, and specific pathways in EVs-mediated drug resistance are not fully understood. This review critically examines recent advancements, highlighting key studies that elucidate the molecular mechanisms of EVs functions. Additionally, innovative therapeutic strategies targeting EVs are explored, including inhibiting EVs biogenesis, engineering EVs for drug delivery, and identifying resistance-inhibiting molecules within EVs. By integrating insights from primary research and proposing new directions for future studies, this review aims to advance the understanding of EVs in cancer biology and foster effective interventions to mitigate drug resistance in cancer therapy.

In this editorial, we will discuss the article by Tang et al published in the recent issue of the World Journal of Gastrointestinal Oncology. They explored an innovative approach to enhancing gemcitabine (GEM) delivery and efficacy using human bone marrow mesenchymal stem cells (HU-BMSCs)-derived exosomes. The manufacture of GEM-loaded HU-BMSCs-derived exosomes (Exo-GEM) has been optimized. The Tang et al's study demonstrated that Exo-GEM exhibits enhanced cytotoxicity and apoptosis-inducing effects compared to free GEM, highlighting the potential of exosome-based drug delivery systems as a more effective and targeted approach to chemotherapy in pancreatic cancer. Additional in vivo studies are required to confirm the safety and effectiveness of Exo-GEM before it can be considered for clinical use.

Pancreatic ductal adenocarcinoma (PDAC) is a malignant neoplasm that typically manifests with subtle clinical manifestations in its early stages and frequently eludes diagnosis until the advanced phases of the disease. The limited therapeutic options available for PDAC significantly contribute to its high mortality rate, highlighting the urgent need for novel biomarkers capable of effectively identifying early clinical manifestations and facilitating precise diagnosis. The pivotal role of cellular exosomes in both the pathogenesis and therapeutic interventions for PDAC has been underscored. Furthermore, researchers have acknowledged the potential of exosomes as targeted drug carriers against regulatory cells in treating PDAC. The present article aims to provide a comprehensive review encompassing recent advancements in utilizing exosomes for elucidating mechanisms underlying disease development, patterns of metastasis, diagnostic techniques and treatment strategies associated with PDAC.

The efficacy of immunotherapy, a pivotal approach in the arsenal of cancer treatment strategies, is contingent on the capacity of effector cells to localize at the tumor site. The navigational capacity of these cells is intricately linked to the homing behaviors of specific cell types. Recent studies have focused on leveraging immune cells and mesenchymal stem cells (MSCs) homing for targeted tumor therapy and incorporating cancer cell homing properties into anti-tumor strategies. However, research and development of immunotherapy based on cancer cell homing remain in their preliminary stages. Enhancing the homing efficiency of effector cells is essential; therefore, understanding the underlying mechanisms and addressing immune resistance within the tumor microenvironment and challenges associated with in vivo therapeutic agent delivery are essential. This review firstly delineates the discovery and clinical translation of the three principal cell-homing behaviors. Secondly, we endeavor to conduct an in-depth analysis of existing research on the homing of immune and stem cells in cancer therapy, with the aim of identifying and understanding of the common applications, potential benefits, barriers, and critical success factors of cellular homing therapies. Finally, based on the understanding of the key factors of cellular homing therapies, we provide an overview and outlook on the enormous potential of harnessing cancer cells' self-homing to treat tumors. Although immunotherapy based on cell-homing behavior warrants further research, it remains a highly competitive treatment modality that can be combined with existing classic anti-cancer therapies. In general, combining the homing properties of cells to optimize their clinical effects is also one of the future research directions in the field of cell transplantation.

Drug resistance is a major challenge in cancer therapy that often leads to treatment failure and disease relapse. Despite advancements in chemotherapeutic agents and targeted therapies, cancers often develop drug resistance, making these treatments ineffective. Extracellular vesicles (EVs) have gained attention for their potential applications in drug delivery because of their natural origin, biocompatibility, and ability to cross biological barriers. Using the unique properties of EVs could enhance drug accumulation at target sites, minimize systemic toxicity, and precisely target specific cells. Here, we discuss the characteristics and functionalization of EVs, the mechanisms of drug resistance, and the applications of engineered EVs to overcome drug resistance. This review provides a comprehensive overview of the advancements in EV-based drug delivery systems and their applications in overcoming cancer drug resistance. We highlight the potential of EV-based drug delivery systems to revolutionize cancer therapy and offer promising strategies for more effective treatment modalities.

Mesenchymal stem cells (MSCs) are a class of protocells that can differentiate into various cell types and have robust replication and renewal capabilities. MSCs secrete various nutritional factors to regulate the microenvironment of tumor tissues. The mechanism by which they inhibit or promote tumor growth may be closely related to MSC-derived exosomes (MSC-Exo). However, the role of MSC-Exo vesicles in tumors remains controversial. This review discusses the potential applications of microRNAs in exosomes derived from MSCs in treating tumors.

Breast cancer is a highly widespread form of malignant tumor characterized by a high rate of recurrence and mortality; it primarily occurs when tumor cells spread to peripheral regions of the body. Macrophages have a significant impact on the proliferation and metastasis of breast cancer. The exosomes generated by these cells exhibit an extensive spectrum of capabilities in suppressing the spread of cancer cells. These feature very specific targeting properties for breast cancer cells and inhibit the proliferation of cancer cells by altering the immune milieu within the tumor. This study investigates methods for developing macrophage-derived exosomes, such as using protein-coupled exosome membranes to protect delivery contents, creating multifunctional biomimetic particles, and utilizing ultrasonic fusion to protect delivery contents. Furthermore, this paper addresses recent advances in producing macrophage exosomes from organic and inorganic materials. In general, targeted treatment for breast cancer could benefit greatly from creating drug delivery systems mediated by macrophage exosomes.

Extracellular vehicles (EVs) are gaining increasing recognition as central contributors to the intricate landscape of the tumor microenvironment (TME). This manuscript provides an extensive examination of the multifaceted roles played by EVs in shaping the TME, with a particular emphasis on their involvement in metastasis, drug resistance, and immune evasion. Metastasis, the process by which cancer cells disseminate to distant sites, remains a formidable challenge in cancer management. EVs, encompassing exosomes and microvesicles, have emerged as critical participants in this cascade of events. They facilitate the epithelial-to-mesenchymal transition (EMT), foster pre-metastatic niche establishment, and enhance the invasive potential of cancer cells. This manuscript delves into the intricate molecular mechanisms underpinning these processes, underscoring the therapeutic potential of targeting EVs to impede metastasis. Drug resistance represents a persistent impediment to successful cancer treatment. EVs are instrumental in intrinsic and acquired drug resistance, acting as mediators of intercellular communication. They ferry molecules like miRNAs and proteins, which confer resistance to conventional chemotherapy and targeted therapies. This manuscript scrutinizes the diverse strategies employed by EVs in propagating drug resistance while also considering innovative approaches involving EV-based drug delivery systems to counteract this phenomenon. Immune evasion is a hallmark of cancer, and EVs are central in sculpting the immunosuppressive milieu of the TME. Tumor-derived EVs thwart immune responses through various mechanisms, including T cell dysfunction induction, the expansion of regulatory T cells (Tregs), and polarization of macrophages towards an immunosuppressive phenotype. In addition, the manuscript explores the diagnostic potential of EVs as biomarkers and their role as therapeutic agents in immune checkpoint blockade therapies. This manuscript provides a comprehensive overview of EV's pivotal role in mediating intricate interactions within the TME, ultimately influencing cancer progression and therapeutic outcomes. A profound understanding of EV-mediated processes in metastasis, drug resistance, and immune evasion opens up promising avenues for developing innovative therapeutic strategies and identifying valuable biomarkers in the ongoing battle against cancer.

In spite of significant advancements in theraputic modalities for hepatocellular carcinoma (HCC), there is still a high annual mortality rate with a rising incidence. Major challenges in the HCC clinical managment are related to the development of therapy resistance, and evasion of tumor cells apoptosis which leading unsatisfactory outcomes in HCC patients. Previous investigations have shown that autophagy plays crucial role in contributing to drug resistance development in HCC. Although, miR-29a is known to counteract authophagy, increasing evidence revealed a down-regulation of miR-29a in HCC patients which correlates with poor prognosis. Beside, evidences showed that miR-29a serves as a negative regulator of autophagy in other cancers. In the current study, we aim to investigate the impact of miR-29a on the autophagy and apoptosis in HCC cells using extracellular vesicles (EVs) as a natural delivery system given their potential in the miRNA delivery both in vitro and in vivo.

Human Wharton's Jelly mesenchymal stromal cell-derived extracellular vesicles were lately isolated through 20,000 or 110,000 × g centrifugation (EV20K or EV110K, respectively), characterized by western blot (WB), scanning electron microscopy (SEM), and dynamic light scattering (DLS). miR-29a was subsequently loaded into these EVs and its loading efficiency was evaluated via RT-qPCR. Comprehensive in vitro and in vivo assessments were then performed on Huh-7 and HepG2 cell lines.

EV20K-miR-29a treatment significantly induces cell apoptosis and reduces both cell proliferation and colony formation in Huh-7 and HepG2 cell lines. In addition, LC3-II/LC3-I ratio was increased while the expression of key autophagy regulators TFEB and ATG9A were downregulated by this treatment. These findings suggest an effective blockade of autophagy by EV20K-miR-29a leading to apoptosis in the HCC cell lines through concomitant targeting of critical mediators within each pathway.

This review explores the evolution of lipid-based nanoparticles (LBNPs) for drug delivery (DD). Herein, LBNPs are classified into liposomes and cell membrane-based nanoparticles (CMNPs), each with unique advantages and challenges. Conventional LBNPs possess drawbacks such as poor targeting, quick clearance, and limited biocompatibility. One of the possible alternatives to overcome these challenges is surface modification of nanoparticles (NPs) with materials such as polyethylene glycol (PEG), aptamers, antibody fragments, peptides, CD44, hyaluronic acid, folic acid, palmitic acid, and lactoferrin. Thus, the main focus of this review will be on the different surface modifications that enable LBNPs to have beneficial properties for DD, such as enhancing mass transport properties, immune evasion, improved stability, and targeting. Moreover, various CMNPs are explored used for DD derived from cells such as red blood cells (RBCs), platelets, leukocytes, cancer cells, and stem cells, highlighting their unique natural properties (e.g., biocompatibility and ability to evade the immune system). This discussion extends to the biomimicking of hybrid NPs accomplished through the surface coating of synthetic (mainly polymeric) NPs with different cell membranes. This review aims to provide a comprehensive resource for researchers on recent advances in the field of surface modification of LBNPs and CMNPs. Overall, this review provides valuable insights into the dynamic field of lipid-based DD systems.

Solid tumors cause 90% of cancers and remain the primary cause of mortality. However, treating solid tumors presents significant challenges due to the complex tumor microenvironment and drug resistance, leading to inadequate treatment targeting and severe side effects. Surgery, radiotherapy, and chemotherapy Although it is an effective method for the treatment of solid tumors, it can lead to organ dysfunction and affect patient prognosis. Therefore, it is imperative to improve treatment precision and organ repair capabilities to manage solid tumors. Mesenchymal stem cell extracellular vesicles (MSC-EVs) have wide application prospects as a new agent for solid tumor therapy. Firstly, MSC-EVs is a derivative of MSCs. It has the function of promoting tissue regeneration by inducing dedifferentiation in surviving cells after injury. Additionally, MSC-EVs offer unique advantages in terms of safety, stability and penetrability, making them a promising extracellular therapeutic modality for solid tumor treatment. Finally, MSC-EVs are able to enhance therapeutic efficacy through engineering strategies. To sum up, this review takes MSC-EVs as its object. And then we discuss recent advancements and engineering strategies in the use of MSC-EVs for soid tumor suppression. This review aims to inspire researchers to devise a new method for effectively treat solid tumors.

Pancreatic cancer remains one of the most lethal malignancies, and has limited effective treatment. Gemcitabine (GEM), a chemotherapeutic agent, is commonly used for clinical treatment of pancreatic cancer, but it has characteristics of low drug delivery efficiency and significant side effects. The study tested the hypothesis that human bone marrow mesenchymal stem cell (MSC)-derived exosomes loaded with GEM (Exo-GEM) would have a higher cytotoxicity against human pancreatic cancer cells by enhancing their apoptosis.

To investigate the cytotoxicity of MSC-derived Exo-GEM against pancreatic cancer cells in vitro.

Exosomes were isolated from MSCs and characterized by transmission electron microscopy and nanoparticle tracking analysis. Exo-GEM through electroporation, sonication, or incubation, and the loading efficiency was evaluated. The cytotoxicity of Exo-GEM or GEM alone against human pancreatic cancer Panc-1 and MiaPaca-2 cells was assessed by MTT and flow cytometry assays.

The isolated exosomes had an average size of 76.7 nm. The encapsulation efficacy and loading efficiency of GEM by electroporation and sonication were similar and significantly better than incubation. The cytotoxicity of Exo-GEM against pancreatic cancer cells was stronger than free GEM and treatment with 0.02 μM Exo-GEM significantly reduced the viability of both Panc-1 and MiaPaca-2 cells. Moreover, Exo-GEM enhanced the frequency of GEM-induced apoptosis in both cell lines.

Human bone marrow MSC-derived Exo-GEM have a potent cytotoxicity against human pancreatic cancer cells by enhancing their apoptosis, offering a promising drug delivery system for improving therapeutic outcomes.

With their low immunogenicity and excellent deliverability, extracellular vesicles (EVs) are promising platforms for drug delivery systems. In this study, hydrophobic molecule loading techniques were developed via an exchange reaction based on supramolecular chemistry without using organic solvents that can induce EV disruption and harmful side effects. To demonstrate the availability of an exchanging reaction to prepare drug-loading EVs, hydrophobic boron cluster carborane (CB) was introduced to EVs (CB@EVs), which is expected as a boron agent for boron neutron capture therapy (BNCT). The exchange reaction enabled the encapsulation of CB to EVs without disrupting their structure and forming aggregates. Single-particle analysis revealed that an exchanging reaction can uniformly introduce cargo molecules to EVs, which is advantageous in formulating pharmaceuticals. The performance of CB@EVs as boron agents for BNCT was demonstrated in vitro and in vivo. Compared to L-BPA, a clinically available boron agent, and CB delivered with liposomes, CB@EV systems exhibited the highest BNCT activity in vitro due to their excellent deliverability of cargo molecules via an endocytosis-independent pathway. The system can deeply penetrate 3D cultured spheroids even in the presence of extracellular matrices. The EV-based system could efficiently accumulate in tumor tissues in tumor xenograft model mice with high selectivity, mainly via the enhanced permeation and retention effect, and the deliverability of cargo molecules to tumor tissues in vivo enhanced the therapeutic benefits of BNCT compared to the L-BPA/fructose complex. All of the features of EVs are also advantageous in establishing anticancer agent delivery platforms.

Exosome-nanoparticle hybrid nanoplatforms, can be prepared by combining exosomes with different types of nanoparticles. The main purpose of combining exosomes with nanoparticles is to overcome the limitations of using each of them as drug delivery systems. Using nanoparticles for drug delivery has some limitations, such as high immunogenicity, poor cellular uptake, low biocompatibility, cytotoxicity, low stability, and rapid clearance by immune cells. However, using exosomes as drug delivery systems also has its own drawbacks, such as poor encapsulation efficiency, low production yield, and the inability to load large molecules. These limitations can be addressed by utilizing hybrid nanoplatforms. Additionally, the use of exosomes allows for targeted delivery within the hybrid system. Exosome-inorganic/organic hybrid nanoparticles may be used for both therapy and diagnosis in the future. This may lead to the development of personalized medicine using hybrid nanoparticles. However, there are a few challenges associated with this. Surface modifications, adding functional groups, surface charge adjustments, and preparing nanoparticles with the desired size are crucial to the possibility of preparing exosome-nanoparticle hybrids. Additional challenges for the successful implementation of hybrid platforms in medical treatments and diagnostics include scaling up the manufacturing process and ensuring consistent quality and reproducibility across various batches. This review focuses on various types of exosome-nanoparticle hybrid systems and also discusses the preparation and loading methods for these hybrid nanoplatforms. Furthermore, the potential applications of these hybrid nanocarriers in drug/gene delivery, disease treatment and diagnosis, and cell/tissue imaging are explained.

In recent years, biologists and clinicians have witnessed prominent advances in in vitro 3D culture techniques related to biomimetic human/animal tissue analogs. Numerous data have confirmed that unicellular and multicellular (tumoroids) tumor spheroids with dense native cells in certain matrices are sensitive and valid analytical tools for drug screening, cancer cell dynamic growth, behavior, etc. in laboratory settings. Angiogenesis/vascularization is a very critical biological phenomenon to support oxygen and nutrients to tumor cells within the deep layer of solid masses. It has been shown that endothelial cell (EC)-incorporated or -free spheroid/tumoroid systems provide a relatively reliable biological platform for monitoring the formation of nascent blood vessels in micron/micrometer scales. Besides, the paracrine angiogenic activity of cells within the spheroid/tumoroid systems can be monitored after being treated with different therapeutic approaches. Here, we aimed to collect recent advances and findings related to the monitoring of cancer angiogenesis using unicellular and multicellular tumor spheroids. Vascularized spheroids/tumoroids can help us in the elucidation of mechanisms related to cancer formation, development, and metastasis by monitoring the main influencing factors.

Despite recent improvements in oncology, diagnosis, and therapy, pancreatic cancer remains extremely difficult to cure due to its aggressive growth pattern with early invasion and distant metastases, chemoresistance, and a lack of effective screening modalities for early detection. Here, novel therapeutic approaches for treating pancreatic cancer are urgently needed. Recently, stem cells have drawn a lot of interest as a possible treatment for pancreatic cancer due to their ability to locate tumors. Though research over the last few decades has revealed some very exciting and promising new treatment approaches, the clinical success of these stem-cell based anti-cancer medicines has been quite limited. The most effective stem cell-mediated therapeutic options will only be available with a deeper understanding of the intricate molecular biology underlying pancreatic cancer and the subsequent identification of cancer stem cells as a novel target that promotes the growth of the cancer and resistance to chemotherapy. This review will highlight the stem cell based anti-cancer therapy targeting pancreatic cancer stem cells and different molecular signaling pathways. A particular focus will be on the therapeutic potential of naïve Stem cells, anti-cancer drug loaded stem cells, genetically engineered stem cells and exosomal miRNA released by stem cells in pancreatic cancer treatment. Similarly, the role of nanotechnology in stem cell based anticancer therapy will be further discussed to better implementation of these cell-based cancer therapy.

Mesenchymal stem cells (MSCs) are recruited by malignant tumor cells to the tumor microenvironment (TME) and play a crucial role in the initiation and progression of malignant tumors. This role encompasses immune evasion, promotion of angiogenesis, stimulation of cancer cell proliferation, correlation with cancer stem cells, multilineage differentiation within the TME, and development of treatment resistance. Simultaneously, extensive research is exploring the homing effect of MSCs and MSC-derived extracellular vesicles (MSCs-EVs) in tumors, aiming to design them as carriers for antitumor substances. These substances are targeted to deliver antitumor drugs to enhance drug efficacy while reducing drug toxicity. This paper provides a review of the supportive role of MSCs in tumor progression and the associated molecular mechanisms. Additionally, we summarize the latest therapeutic strategies involving engineered MSCs and MSCs-EVs in cancer treatment, including their utilization as carriers for gene therapeutic agents, chemotherapeutics, and oncolytic viruses. We also discuss the distribution and clearance of MSCs and MSCs-EVs upon entry into the body to elucidate the potential of targeted therapies based on MSCs and MSCs-EVs in cancer treatment, along with the challenges they face.

Pancreatic cancer remains one of the most lethal diseases worldwide. Cancer-derived exosomes, benefiting from the protective role of the lipid membrane, exhibit remarkable stability in the circulatory system. These exosomes, released by tumor microenvironment, contain various biomolecules such as proteins, RNAs, and lipids that plays a pivotal role in mediating distant communication between the local pancreatic tumor and other organs or tissues. They facilitate the transfer of oncogenic factors to distant sites, contributing to the compromised body immune system, distant metastasis, diabetes, cachexia, and promoting a microenvironment conducive to tumor growth and metastasis in pancreatic cancer patients. Beyond their intrinsic roles, circulating exosomes in peripheral blood can be detected to facilitate accurate liquid biopsy. This approach offers a novel and promising method for the diagnosis and management of pancreatic cancer. Consequently, circulating exosomes are not only crucial mediators of systemic cell-cell communication during pancreatic cancer progression but also hold great potential as precise tools for pancreatic cancer management and treatment. Exosome-based liquid biopsy and therapy represent promising advancements in the diagnosis and treatment of pancreatic cancer. Exosomes can serve as drug delivery vehicles, enhancing the targeting and efficacy of anticancer treatments, modulating the immune system, and facilitating gene editing to suppress tumor growth. Ongoing research focuses on biomarker identification, drug delivery systems, and clinical trials to validate the safety and efficacy of exosome-based therapies, offering new possibilities for early diagnosis and precision treatment in pancreatic cancer. Leveraging the therapeutic potential of exosomes, including their ability to deliver targeted drugs and modulate immune responses, opens new avenues for innovative treatment strategies.

Today, cancer treatment is one of the main challenges for researchers. The main cause of tumor cell formation is mutations that lead to uncontrolled proliferation and inhibition of apoptosis in malignant cells. Tumor cells also create a microenvironment that can suppress the immune system cells' responses through various methods, including producing soluble factors and cell-to-cell communication. After being produced from tumor cells, exosomes can also affect the functions of other cells in this microenvironment. Various studies have shown that exosomes from different sources, including tumor cells and immune cells, can be used to treat cancers due to their characteristics. Since tumor cells are rich sources of various types of tumor peptides, they can induce anti-tumor responses. Immune cells also produce exosomes that mimic the functions of their cells of origin, such that exosomes derived from NK cells and CTLs can directly lead to their apoptosis after merging with tumor cells. However, many researchers have pointed out that naïve exosomes have a limited therapeutic function, and their therapeutic potential can be increased by manipulating and engineering them. There are various methods to modify exosomes and improve their therapeutic potential. In general, these methods are divided into two parts, which include changing the cell of origin of the exosome and encapsulating the exosome to carry different drugs. In this review, we will discuss the studies on the therapeutic use of naive and engineered exosomes and provide an update on new studies in this field.

Exosomes play a crucial role in the progression and spread of pancreatic cancer, serving not only as promoters of tumor growth and organ-specific metastasis but also as promising biomarkers and targets for treatment. These nano vesicles enhance intercellular communication by transferring bioactive molecules, such as proteins and RNAs, between cells. This process significantly affects cancer cell dynamics, including their proliferation, migration, and invasion, while also contributing to drug resistance. Our review focuses on the crucial interactions between cancer cells and fibroblasts mediated by exosomes within the pancreatic cancer microenvironment. We delve into how exosomes from both cancer-associated fibroblasts and the cancer cells themselves drive tumor progression through various mechanisms, such as epithelial-mesenchymal transition and facilitating metastasis to specific organs like the lungs and liver. The potential of leveraging exosomes for therapeutic interventions is also explored, highlighting the importance of understanding their role in cell communication as a step forward in developing more effective pancreatic cancer treatments.

Targeting actionable mutations in oncogene-driven cancers and the evolution of immuno-oncology are the two prominent revolutions that have influenced cancer treatment paradigms and caused the emergence of precision oncology. However, intertumoral and intratumoral heterogeneity are the main challenges in both fields of precision cancer treatment. In other words, finding a universal marker or pathway in patients suffering from a particular type of cancer is challenging. Therefore, targeting a single hallmark or pathway with a single targeted therapeutic will not be efficient for fighting against tumor heterogeneity. Mesenchymal stem cells (MSCs) possess favorable characteristics for cellular therapy, including their hypoimmune nature, inherent tumor-tropism property, straightforward isolation, and multilineage differentiation potential. MSCs can be loaded with various chemotherapeutics and oncolytic viruses. The combination of these intrinsic features with the possibility of genetic manipulation makes them a versatile tumor delivery vehicle that can be used for in vivo selective tumor delivery of various chemotherapeutic and biological therapeutics. MSCs can be used as biofactory for the local production of chemical or biological anticancer agents at the tumor site. MSC-mediated immunotherapy could facilitate the sustained release of immunotherapeutic agents specifically at the tumor site, and allow for the achievement of therapeutic concentrations without the need for repetitive systemic administration of high therapeutic doses. Despite the enthusiasm evoked by preclinical studies that used MSC in various cancer therapy approaches, the translation of MSCs into clinical applications has faced serious challenges. This manuscript, with a critical viewpoint, reviewed the preclinical and clinical studies that have evaluated MSCs as a selective tumor delivery tool in various cancer therapy approaches, including gene therapy, immunotherapy, and chemotherapy. Then, the novel nanotechnology and bioengineering approaches that can improve the potency of MSC for tumor targeting and overcoming challenges related to their low localization at the tumor sites are discussed.

Sonic Hedgehog (SHH) is a fundamental signaling pathway that controls tissue reconstruction, stem cell biology, and differentiation and has a role in gut tissue homeostasis and development. Dysregulation of SHH leads to the development of HCC.

The present study was conducted to compare the effects of mesenchymal stem cells (MSCs) and curcumin on SHH molecular targets in an experimental model of HCC in rats. One hundred rats were divided equally into the following groups: control group, HCC group, HCC group received MSCs, HCC group received curcumin, and HCC group received MSCs and curcumin. Histopathological examinations were performed, and gene expression of SHH signaling target genes (SHH, PTCH1, SMOH, and GLI1) was assessed by real-time PCR in rat liver tissue. Results showed that SHH target genes were significantly upregulated in HCC-untreated rat groups and in MSC-treated groups, with no significant difference between them. Administration of curcumin with or without combined administration of MSCs led to a significant down-regulation of SHH target genes, with no significant differences between both groups. As regards the histopathological examination of liver tissues, both curcumin and MSCs, either through separate use or their combined use, led to a significant restoration of normal liver pathology.

In conclusion, SHH signaling is upregulated in the HCC experimental model. MSCs do not inhibit the upregulated SHH target genes in HCC. Curcumin use with or without MSCs administration led to a significant down-regulation of SHH signaling in HCC and a significant restoration of normal liver pathology.

Pancreatic cancer is a prevalent lethal gastrointestinal cancer that generally does not show any symptoms until it reaches advanced stages, resulting in a high mortality rate. People at high risk, such as those with a family history or chronic pancreatitis, do not have a universally accepted screening protocol. Chemotherapy and radiotherapy demonstrate limited effectiveness in the management of pancreatic cancer, emphasizing the urgent need for innovative therapeutic strategies. Recent studies indicated that the complex interaction among pancreatic cancer cells within the dynamic microenvironment, comprising the extracellular matrix, cancer-associated cells, and diverse immune cells, intricately regulates the biological characteristics of the disease. Additionally, mounting evidence suggests that EVs play a crucial role as mediators in intercellular communication by the transportation of different biomolecules, such as miRNA, proteins, DNA, mRNA, and lipids, between heterogeneous cell subpopulations. This communication mediated by EVs significantly impacts multiple aspects of pancreatic cancer pathogenesis, including proliferation, angiogenesis, metastasis, and resistance to therapy. In this review, we delve into the pivotal role of EV-associated miRNAs in the progression, metastasis, and development of drug resistance in pancreatic cancer as well as their therapeutic potential as biomarkers and drug-delivery mechanisms for the management of pancreatic cancer.

Pulmonary fibrosis (PF) is a chronic, progressive and irreversible interstitial lung disease that seriously threatens human life and health. Our previous study demonstrated the unique superiority of traditional Chinese medicine cryptotanshinone (CTS) combined with sustained pulmonary drug delivery for treating PF. In this study, we aimed to enhance the selectivity, targeting efficiency and sustained-release capability based on this delivery system. To this end, we developed and evaluated CTS-loaded modified liposomes-chitosan (CS) microspheres SM(CT-lipo) and liposome-exosome hybrid bionic vesicles-CS microspheres SM(LE). The prepared nano-in-micro particles system integrates the advantages of the carriers and complements each other. SM(CT-lipo) and SM(LE) achieved lung myofibroblast-specific targeting through CREKA peptide binding specifically to fibronectin (FN) and the homing effect of exosomes on parent cells, respectively, facilitating efficient delivery of anti-fibrosis drugs to lung lesions. Furthermore, compared with daily administration of conventional microspheres SM(NC) and positive control drug pirfenidone (PFD), inhaled administration of SM(CT-lipo) and SM(LE) every two days still attained similar efficacy, exhibiting excellent sustained drug release ability. In summary, our findings suggest that the developed SM(CT-lipo) and SM(LE) delivery strategies could achieve more accurate, efficient and safe therapy, providing novel insights into the treatment of chronic PF.

The gastrointestinal tract can be affected by a number of diseases that pancreatic cancer (PC) is a malignant manifestation of them. The prognosis of PC patients is unfavorable and because of their diagnosis at advanced stage, the treatment of this tumor is problematic. Owing to low survival rate, there is much interest towards understanding the molecular profile of PC in an attempt in developing more effective therapeutics. The conventional therapeutics for PC include surgery, chemotherapy and radiotherapy as well as emerging immunotherapy. However, PC is still incurable and more effort should be performed. The molecular landscape of PC is an underlying factor involved in increase in progression of tumor cells. In the presence review, the newest advances in understanding the molecular and biological events in PC are discussed. The dysregulation of molecular pathways including AMPK, MAPK, STAT3, Wnt/β-catenin and non-coding RNA transcripts has been suggested as a factor in development of tumorigenesis in PC. Moreover, cell death mechanisms such as apoptosis, autophagy, ferroptosis and necroptosis demonstrate abnormal levels. The EMT and glycolysis in PC cells enhance to ensure their metastasis and proliferation. Furthermore, such abnormal changes have been used to develop corresponding pharmacological and nanotechnological therapeutics for PC.

This review aims to provide a quantitative and qualitative bibliometric analysis of literature from 2013 to 2023 on the role of exosomes in PC, with the goal of identifying current trends and predicting future hotspots.

We retrieved relevant publications concerning exosomes in PC, published between 2013 and 2023, from the Web of Science Core Collection. Bibliometric analyses were conducted using VOSviewer(1.6.19), CiteSpace(6.2.R4), and Microsoft Excel (2019).

A total of 624 papers were analyzed, authored by 4017 researchers from 55 countries/regions and 855 institutions, published in 258 academic journals. China (n=285, 34.42%) and the United States (n=183, 24.87%) were the most frequent contributors and collaborated closely. However, publications from China had a relatively low average number of citations (41.45 times per paper). The output of Shanghai Jiao Tong University ranked first, with 28 papers (accounting for 4.5% of the total publications). Cancers (n=31, 4.9%); published the most papers in this field. Researcher Margot Zoeller published the most papers (n=12) on this topic. Research hotspots mainly focused on the mechanisms of exosomes in PC onset and progression, the role of exosomes in PC early diagnosis and prognosis, exosomes promote the development of PC chemoresistance, and potential applications of exosomes as drug carriers for PC therapies. We observed a shift in research trends, from mechanistic studies toward clinical trials, suggesting that clinical applications will be the focus of future attention. Emerging topics were pancreatic stellate cells, diagnostic biomarkers, mesenchymal stem cells, extracellular vesicles.

Our scientometric and visual analysis provides a comprehensive overview of the literature on the role of exosomes in PC published during 2013-2023. This review identifies the frontiers and future directions in this area over the past decade, and is expected to provide a useful reference for researchers in this field.

The incidence and mortality of pancreatic ductal adenocarcinoma (PDAC) have increased. Exosomes, as a regulatory mode of intercellular communication, contain lncRNAs. SOX21-AS1 has been studied in other cancers, and its expression is elevated in PDAC, but its role in PDAC remains unclear. First, we analyzed the expression of lncRNAs in PDAC tissues and nontumor tissues through the TCGA database. Next, the results of the RT-qPCR experiment confirmed the prediction that the expression of SOX21-AS1 was elevated in PDAC tissues. In vivo and in vitro cell function assays confirmed that the degree of malignancy of PDAC was proportional to the expression of SOX21-AS1. In addition, through exosome isolation and uptake experiments, we first found that PDAC could secrete exosomal SOX21-AS1 and play an angiogenic role in HUVECs. Subsequently, the relationship between SOX21-AS1, miR-451a and epiregulin (EREG) was verified through database prediction and analysis and RIP assays. Finally, functional recovery assays in vivo and in vitro verified that SOX21-AS1 regulates the expression of EREG through combination with miR-451a and thus promotes the malignancy of PDAC. SOX21-AS1 was upregulated in PDAC. The upregulation of SOX21-AS1 can stimulate the proliferation, migration, invasion, stemness and epithelial-mesenchymal transition (EMT) progression of PDAC cells. Furthermore, PDAC cells secrete exosomal SOX21-AS1, which is absorbed by HUVECs and promotes angiogenesis. Our study first identified that SOX21-AS1 promotes the malignancy of PDAC through the SOX21-AS1/miR-451a/EREG axis, and also that exosomal SOX21-AS1 promotes angiogenesis in PDAC.

Tumors desmoplastic microenvironments are characterized by abundant stromal cells and extracellular matrix (ECM) deposition. Cancer-associated fibroblasts (CAFs), as the most abundant of all stromal cells, play significant role in mediating microenvironments, which not only remodel ECM to establish unique pathological barriers to hinder drug delivery in desmoplastic tumors, but also talk with immune cells and cancer cells to promote immunosuppression and cancer stem cells-mediated drug resistance. Thus, CAFs mediated desmoplastic microenvironments will be emerging as promising strategy to treat desmoplastic tumors. However, due to the complexity of microenvironments and the heterogeneity of CAFs in such tumors, an effective deliver system should be fully considered when designing the strategy of targeting CAFs mediated microenvironments. Engineered exosomes own powerful intercellular communication, cargoes delivery, penetration and targeted property of desired sites, which endow them with powerful theranostic potential in desmoplastic tumors. Here, we illustrate the significance of CAFs in tumors desmoplastic microenvironments and the theranostic potential of engineered exosomes targeting CAFs mediated desmoplastic microenvironments in next generation personalized nano-drugs development.