Gelatin/Lignin Hydrogel Loaded with Mesenchymal Stem Cell-Derived Exosomes Enriched in Microrna-185 Inhibits Progression of Oral Cancer

<b>Purpose:</b> Due to the lack of effective local therapeutic strategies for oral squamous cell carcinoma (OSCC), this study aimed to develop a novel gelatin/lignin hydrogel loaded with mesenchymal stem cell (MSC)-derived exosomes enriched in microRNA-185 (miR-185 EV) for intraoral delivery, followed by systematic evaluation of its therapeutic efficacy and underlying molecular mechanisms. <b>Materials and Methods:</b> The gelatin/lignin hydrogel was prepared and subsequently loaded with miR-185 EV. The physicochemical properties of the hydrogel, including microstructure, swelling behavior, chemical composition, and rheological characteristics, were systematically evaluated. Next, the stability, viscosity, biocompatibility, and exosome release kinetics of the hydrogel were further assessed. A 4-nitroquinoline-1-oxide (4NQO)-induced mouse tongue carcinogenesis model was established to assess the in vivo antitumor activity of the hydrogel via intraoral administration. Moreover, a proteomic analysis was conducted to investigate the molecular mechanisms of miR-185 EV on OSCC. <b>Results:</b> The miR-185 EV-loaded gelatin/lignin hydrogel exhibited favorable physicochemical properties, stability, and biocompatibility while prolonging the tissue retention time of miR-185 EV. In vivo antitumor efficacy experiments showed that the miR-185 EV-loaded hydrogel significantly inhibited tumor occurrence and alleviated epithelial dysplasia. Immunohistochemical analyses revealed significant suppression of tumor proliferation and epithelial-mesenchymal transition (EMT) of the hydrogel. Proteomic analysis indicated that miR-185 EV suppressed OSCC progression by downregulating interleukin-1β (IL-1β), consequently inhibiting the NF-κB signaling pathway. <b>Conclusion:</b> The findings demonstrate the successful development of the miR-185 EV-loaded gelatin/lignin hydrogel that represents an effective nanomedicine platform for intraoral drug delivery, providing a promising strategy for the clinical treatment of OSCC.