Immunogenic Extracellular Vesicles Derived from Endoplasmic Reticulum-Stressed Tumor Cells: Implications as the Therapeutic Cancer Vaccine.

Tumor-derived extracellular vesicles (TDEs) have potential for therapeutic cancer vaccine applications since they innately possess tumor-associated antigens, mediate antigen presentation, and can incorporate immune adjuvants for enhanced vaccine efficacy. However, the original TDEs also contain immune-suppressive proteins. To address this, we proposed a simple yet powerful preconditioning method to improve the overall immunogenicity of the TDEs. This approach involved inducing endoplasmic reticulum (ER) stress on parental tumor cells via N-glycosylation inhibition with tunicamycin. The generated immunogenic TDEs (iTDEs) contained down-regulated immunosuppressive proteins and up-regulated immune adjuvants, effectively activating dendritic cells (DCs) in vitro. Furthermore, in vivo evidence from a tumor-bearing mouse model showed that iTDEs activated DCs, enabling cytotoxic T lymphocytes (CTLs) to target tumors, and eventually established a systemic antitumor immune response. Additionally, iTDEs significantly delayed tumor recurrence in a postsurgery model compared with control groups. These findings highlight the immense potential of our strategy for utilizing TDEs to develop effective cancer vaccines.

Stem Cell-Derived Extracellular Vesicle-Bearing Injectable Hydrogel for Collagen Generation in Dermis.

Despite the remarkable advances of dermal fillers that reduce wrinkles caused by dermis thickness reduction, they still lack effective hydrogel systems that stimulate collagen generation along with injection convenience. Here, we develop a stem cell-derived extracellular vesicle (EV)-bearing thermosensitive hydrogel (EVTS-Gel) for effective in vivo collagen generation. The TS-Gel undergoes sol-gel transition at 32.6 °C, as demonstrated by the storage and loss moduli crossover. Moreover, the TS-Gel and the EVTS-Gel have comparable rheological properties. Both hydrogels are injected in a sol state; hence, they require lower injection forces than conventional hydrogel-based dermal fillers. When locally administered to mouse skin, the TS-Gel extends the retention time of EVs by 2.23 times. Based on the nature of the controlled EV release, the EVTS-Gel significantly inhibits the dermis thickness reduction caused by aging compared to the bare EV treatment for 24 weeks. After a single treatment, the collagen layer thickness of the EVTS-Gel-treated dermis becomes 2.64-fold thicker than that of the bare EV-treated dermis. Notably, the collagen generation efficacy of the bare EV is poorer than that of the EVTS-Gel of a 10× lesser dose. Overall, the EVTS-Gel shows potential as an antiaging dermal filler for in vivo collagen generation.