Paclitaxel-Loaded Phycocyanin Nanoformulation Attenuates EMT-Mediated Metastasis in Glioblastoma

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Abstract Glioblastoma is the most aggressive primary brain tumor and is characterized by rapid progression, therapeutic resistance, and poor patient survival. Although paclitaxel exhibits potent antitumor activity, its clinical translation for glioblastoma remains limited by poor aqueous solubility, restricted blood–brain barrier penetration, systemic toxicity, and persistent epithelial–mesenchymal transition-driven invasion. Here, we engineered a phycocyanin-based, biodegradable nanoparticle encapsulating paclitaxel to improve drug delivery while simultaneously modulating the molecular pathways underlying glioblastoma progression. The nanocarrier exhibited favorable physicochemical characteristics, high colloidal stability, sustained drug release, and excellent biocompatibility, resulting in enhanced cellular internalization and significantly greater cytotoxicity than free paclitaxel in glioblastoma cells. This nanoenabled intracellular delivery promoted mitochondrial dysfunction and reactive oxygen species generation, leading to robust apoptotic cell death. Mechanistically, nanoparticle-mediated paclitaxel delivery induced a previously unrecognized BMI1-dependent reduction in SOX2 phosphorylation, destabilizing SOX2 and reducing its occupancy at the Twist1 promoter, thereby suppressing epithelial–mesenchymal transition and invasive phenotypes. In a glioblastoma xenograft model, the phycocyanin nanoparticle formulation achieved superior antitumor efficacy compared with free paclitaxel, significantly reducing tumor burden while exhibiting minimal systemic toxicity, as demonstrated by stable body weight and the absence of detectable histopathological abnormalities in major organs. Collectively, this study establishes a naturally derived phycocyanin nanoplatform that integrates sustained drug delivery with epigenetic regulation of the BMI1–SOX2–Twist1 signaling axis, highlighting how nanocarrier engineering can enhance therapeutic bioavailability while overcoming epithelial–mesenchymal transition-associated therapeutic resistance in glioblastoma.