Cátia Domingues, Ivana Jarak, Jorge F. J. Coelho, Rui A. Carvalho, Francisco Veiga, Carla Vitorino, Marı́lia Dourado, Ana Figueiras
Oral squamous cell carcinoma (OSCC) treatment is challenged by disrupted microRNA (miRNA) regulation, making efficient miRNA delivery essential. Here, we synthesized and screened Pluronic-polyethylenimine (Pluronic-PEI) nanocarriers for miRNA delivery in OSCC. Among several Pluronic variants, only L121 formed stable, fully cross-linked micellar nanogels with low-molecular-weight PEI (1.8 kDa), designated PP03. Its monomodal size, rough 3D morphology, and zeta potential > +30 mV provide colloidal stability and allow electrostatic miRNA complexation. The presence of a pH-sensitive ester linkage may enable endosomal escape through PEI's proton sponge effect, combined with Pluronic-mediated osmotic modulation, which promotes the release of the therapeutic cargo at the site of action. These findings may lead to the PP03 outstanding profile in delivering miRNA100, which significantly reduced OSCC cell metabolic activity in 2D and 3D cultures and decreased spheroid size, particularly in highly metastatic models. Moreover, the noticeable mucoadhesion properties of PP03 and its hemocompatibility encourage its versatile application for oromucosal and intravenous administration. These results underscore the importance of polymer chemistry in developing functional miRNA nanocarriers to enhance oral cancer treatment.