, cytokines modifiable at its surface and in its cargos versatile delivery modalities stable

The gap

Evidence profile

Sourced from the future work and limitations of the source papers, classified as general, drawn from work published between 2024 and 2026, spanning 4 journals. Those papers have been cited 628 times in total.

Supporting evidence — 4 representative gaps

• Mesenchymal Stem Cell Therapy in Parkinson’s Disease: A Comprehensive Review (2026) · Cureus · doi

  Future directions include multicenter trials with sufficient power, uniformity of stem cell products (particularly MSCs), and synchronous endpoints [28]. Assessment of potency-based dosing (linking in vitro quantitative functional assays of live tissue to in vivo response) should be associated with treatment arm performance metrics in the phase 2 study [18]. Use of multiple biomarkers to determine the mechanism of action (immunomodulation vs. neurotrophic support vs. EVs) should also be explored [28]. MSC-exosome or MSC-based therapies, as possible safer and more controllable “cell-free” biopharmaceutical products, should be investigated through extensive clinical evaluation [28]. Combined approaches (i.e., MSCs/exosomes + rehabilitation; combined MSCs/exosomes + neuromodulation therapy; combined MSCs/exosomes + targeted anti-inflammatory therapy) should also be evaluated using factorial designs [28].

  generalfuture work
  Keywords: mscs combined exosomes cell products based therapy future directions include multicenter trials sufficient power uniformity
• Clinical applications of stem cell-derived exosomes (2024) · Signal Transduction and Targeted Therapy · cited 615× · doi

  , cytokines modifiable at its surface and in its cargos versatile delivery modalities stable for long-term storage and transport negligible risk of tumorigenesis and immune response lack of ethical issues no standardized protocol for purification and storage relatively low yield for large scale manufacturing no industry-standard quality specifications insufficient regulatory control exosomes inherit similar therapeutic effects from their parental cell of origin, e.

  generallimitations
  Keywords: storage cytokines modi able surface cargos versatile delivery modalities stable long term transport negligible risk
• Exosomes in HPV-Associated Cancers: From Biomarkers to Engineered Therapeutics (2025) · Cancers · cited 12× · doi

  Despite the growing interest in exosomes as diagnostic and therapeutic agents in HPV- associated cancers, several important challenges remain. First, there is a need to standardize exosome isolation, quantification, and characterization protocols [91,92]. In the mentioned studies, patient exosomes are derived from different sources: body fluids like blood plasma, saliva, urine, and from cervicovaginal lavage (Figure 1) [13,30,51,60,93,94]. Blood plasma is the most preferred, but there is no comparison between the effectiveness of different sources and how their utility could differ, and for each study, the most convenient source is chosen for analysis. Methodological consistency is essential to ensure reproducibility and clinical translatability. The Minimal Information for Studies of Extracellular Vesicles (MI- SEV) guidelines, developed by the International Society for Extracellular Vesicles, provide standardized criteria for EV isolation, characterization, and reporting [95,96]. Applying these recommendations is particularly important in the context of HPV-driven malignan- cies, where biomarker studies often vary widely in sample type, EV isolation method, and analytical approach. By adhering to MISEV, researchers can generate more comparable datasets, facilitate meta-analyses, and accelerate the translation of exosome research into reliable diagnostic and prognostic tools for cervical and other HPV-associated cancers. In addition, no consensus is present on which exosomal markers need to be checked for HPV infection characterization or the related tumor stage/behavior determination. Because exo- somal cargo is very heterogeneous and closely dependent on the cellular context, singular isolation of specific biomolecules is hard [97,98]. Without standardization of the isolation and analysis processes, clinical reproducibility and approval will remain elusive. Recent evidence also highlights the importance of considering the molecular mecha- nisms mediated by HPV-associated exosomes when designing future studies. Exosomes derived from HPV(+) cancers carry immunomodulatory molecules such as PD-L1, TGF-β, CD47, and miR-1468-5p, which contribute to immune evasion by suppressing cytotoxic T cell activity and promoting lymphangiogenesis [27–33]. At the same time, unique ex- osomal cargo in HPV+ tumors may partly explain why they remain more responsive to immunotherapy compared to HPV− cancers [25,34,35]. Elucidating these dual immunolog- ical effects could help refine exosome-based biomarkers for predicting treatment response and immune checkpoint efficacy. Cancers 2025, 17, 3386 20 of 26 Exosomes are also active drivers of epithelial–mesenchymal transition (EMT) and metastasis in HPV-related cancers. Cargo such as EGFR, TWIST1, SNAI1/2, and pro- metastatic miRNAs (e.g., miR-10b-5p, miR-221-3p) promote motility, invasion, and extracel- lular matrix remodeling [27,42,44]. Similarly, exosome-mediated angiogenesis, involving molecules like Wnt7b mRN

  generalfuture work
  Keywords: cancers exosomes isolation exosome associated remain characterization cargo diagnostic important there need derived different sources
• Mesenchymal stem cells-derived extracellular vesicles as a novel drug delivery carrier: engineering strategies and clinical safety estimation (2026) · Frontiers in Molecular Biosciences · cited 1× · doi

  To address these challenges, future research should focus on optimizing the delivery routes of MSC-EVs based on disease characteristics and their pharmacokinetic profiles. Current known techniques, such as nebulized inhalation, microneedle therapy, and local injection, hold promise for enhancing the therapeutic effects of MSC-EVs. Furthermore, future clinical trials should aim to conduct large-scale, multicenter, and randomized controlled studies to broaden the application scope of MSC-EVs as drug delivery carriers and promote their widespread use in clinical treatment. As a clinical drug, MSC-EVs need to clearly define their cellular origin, lipid membrane vesicle structure, and physicochemical integrity, and establish quantifiable biomarkers (such as specific protein profiles) to confirm identity and purity. Currently, there is a lack of a globally unified definition of MSC-EVs and quantitative standards for key characteristics (van Balkom et al., 2019). A 2024 review by Wang et al. systematically examined the global regulatory landscape of exosomes as biologic medicines, highlighting the chemistry, manufacturing, and control (CMC) requirements imposed across different jurisdictions, as well as the inherent challenges of demonstrating pharmacokinetics and therapeutic efficacy to regulatory agencies (Wang C. K. et al., 2024). A subsequent 2025 review on worldwide EVs-based drug development guidelines further noted that regulatory authorities in the European Union, the United States, and China are actively advancing technical frameworks to address the unique complexities of EVs-based products (Xu et al., 2025). The European Union follows the framework for advanced therapeutic medicinal products (ATMP) and conducts evaluations in accordance with the regulatory requirements for cell therapy products. Guided by the relevant regulations of The European Union Regulation 1394/2007, it focuses on aspects such as the production process, quality control, non- clinical research, and clinical research of EVs drugs (Varderidou- Minasian and Lorenowicz, 2020; Joyce et al., 2023). The FDA of the United States tends to regulate based on biological products, emphasizing the quality of CMC data and the IND application, and focusing on the safety, efficacy and quality controllability of EVs drugs (Mitrani et al., 2021). The National Medical Products Administration of China has incorporated MSC-EVs into the ATMP framework and implemented classified management, emphasizing full life-cycle control (Zhang et al., 2024; Yuan et al., 2025). As regulatory authorities worldwide continue to develop and refine technical guidelines specific to EVs-based therapeutics, international organizations such as the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) are expected to play a pivotal role in fostering regulatory convergence and promoting the global harmonization of standards for EVs-based drug products.

  generalfuture work
  Keywords: based regulatory products clinical drug therapeutic control requirements european union technical quality address challenges future

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