The relative contribution of exosomal PD-L1 versus

The gap

Evidence profile

Stated in the future work and limitations and discussion sections of the source papers, classified as general, drawn from work published between 2024 and 2026, spanning 3 journals. Those papers have been cited 1,230 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].

  generalstated in future workevidence 5/5
  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

  Stem cell therapy multilineage differentiation potential short-lived viability and low engraftment after injection applicable to the treatment for a wide range of diseases stringent storage and transport requirements extensive accumulation of laboratory and clinical data tumorigenic potential easy to isolate and possible for mass-production well-developed regulatory guidelines infusion toxicity immunogenicity ethical issues Stem cell-derived exosome therapy comparable therapeutic effects to stem cells but much smaller batch-to-batch inconsistency more concentrated functional cargos, e.g., 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.g., tissue regeneration, anti-inflammation and immunomodulation.12,16–18 In this work, we will dissect relevant publications from the last five years in order to present a comprehensive, up-to-date, specialty-specific and disease-oriented review (Fig. 2). Our aim is to bridge the gap that currently exists between surgeons, nanomedicine practitioners, and stem cell researchers. GENERAL BACKGROUND OF EXOSOMES AND EXOSOME THERAPY Biogenesis, composition, and uptake of exosomes Exosomes differ from other types of primary extracellular vesicles (e.g., apoptotic bodies and microvesicles) in terms of size, content, and production mechanism.19 The most popularly accepted mechanism of exosome formation, i.e., an endosomal route, is as follows (Fig. 1a). The initial endosomes are produced by cell membrane invagination during which the bioactive substances begin to accumulate within the early sorting endosomes. The late sorting endosomes then form multivesicular bodies (MVBs) after a second indentation. Finally, fuse with the cell membrane, releasing the carried exosomes to the outside. Nonendosomal such as plasma route of exosome biogenesis, membrane budding, has also been reported.20 the MVBs including proteins, glycoconjugates, As the three major exosome databases (i.e., ExoCarta, Vesiclepedia, and EVpedia) summarize, exosomes contain numerous molecules, lipids, nucleic acids, metabolites, and other bioactive substances (Fig. 1b). The examples of each category and the corresponding functions have been thoroughly reviewed elsewhere.21,22 On the one hand, exosomes comprise a complex protein network including external proteins (e.g., tetraspanins, antigen-presenting complexes, and adhesion molecules) and internal proteins (e.g., heat shock proteins, ESCRT machinery, cytokines and chemokines, and membrane transporters).23 On the other hand, as the most abundant in human exosomal nucleic acids, microRNA (mRNA) could participate in hematopoiesis, exocytosis, and nerve and vascular cellular communication.24 exosome-mediated regeneration through There are various uptake mechanisms once exosomes reach the recipient cell, all of which can be categorized into membrane fusion, receptor interaction, and internalization21 (Fig. 1b).

  generalstated in limitationsevidence 5/5
  Keywords: exosomes cell exosome membrane stem proteins therapy storage cargos endosomes potential transport production regulatory ethical
• Clinical applications of stem cell-derived exosomes (2024) · Signal Transduction and Targeted Therapy · cited 615× · doi

  Exosomes have been pursued recently as a cell-free alternative to stem cell-based therapy. ESC-, iPSC-, HSC-, MSC-, NSC- and EPCderived exosomes are of particular interest, partially due to the pluripotency or multipotency of their parental cells. After going through production and purification with or without modification, stem cell-derived exosomes have demonstrated tremendous potential in treating numerous diseases encountered during surgical practice. These are exemplified by disorders in orthopedic fracture, osteoarthritis, and spinal cord injury); surgery (e.g., neurosurgery (e.g., ischemic stroke, traumatic brain injury, and Alzheimer’s disease); plastic surgery (e.g., wound healing); general surgery (e.g., acute liver injury); cardiothoracic surgery (e.g., myocardial infarction); urology (e.g., chronic kidney disease); head and neck surgery (e.g., sensorineural hearing loss); ophthalmology (e.g., acquired optic neuropathies), and gynecology (e.g., primary ovarian insufficiency).

  generalstated in future workevidence 5/5
  Keywords: surgery exosomes cell injury stem derived cation disease pursued recently free alternative based therapy ipsc
• Exosome-orchestrated network in gastric cancer: mechanisms, immune regulation, biomarkers and therapeutic vehicles (2026) · Frontiers in Cell and Developmental Biology · doi

  The relative contribution of exosomal PD-L1 versus surface PD-L1 on tumor cells to systemic immunosuppression remains unclear. Their performance in primary care screening settings, where GC prevalence is low, has not been tested. Reimbursement pathways have not been established. Head-to-head comparisons with clinically approved nanocarriers are lacking, and the projected cost per dose for engineered exosomes exceeds that of monoclonal antibodies.

  generalstated in discussionevidence 5/5
  Keywords: head relative contribution exosomal versus surface tumor cells systemic immunosuppression remains unclear performance primary care

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