EGFR-Targeted RNA-Exosome Nanoparticles Delivering Paclitaxel Suppress Colorectal Cancer via PRELP Upregulation.

Abstract

Targeted drug delivery remains a major challenge in the treatment of colorectal cancer (CRC), particularly in overcoming tumor immune evasion. Exosome-based nanocarriers have shown considerable promise due to their tumor-targeting capability and immunomodulatory potential. In this study, EGFR-targeted RNA-exosome composite paclitaxel (PTX) nanoparticles (RNA-Exo-PTX) were constructed and characterized. Their antitumor effects and mechanisms were evaluated using colorectal cancer cell models, T-cell co-culture systems, and nude mouse xenografts. In vitro assays, flow cytometry, ELISA, and molecular analyses were used to assess cell proliferation, apoptosis, migration, and immune-related responses, while in vivo effects were examined by RT-qPCR, Western blotting, immunofluorescence, and immunohistochemistry. RNA-Exo-PTX exhibited a uniform size distribution, preserved exosomal characteristics, and demonstrated high RNA loading efficiency. Compared with free paclitaxel, RNA-Exo-PTX markedly inhibited colorectal cancer cell proliferation, migration, and clonogenic capacity while promoting apoptosis; these effects were partially attenuated upon EGFR or PRELP interference. In the T-cell co-culture system, RNA-Exo-PTX treatment significantly upregulated PRELP expression in colorectal cancer cells and enhanced T-cell activation, as evidenced by increased secretion of IFN-γ, granzyme B, and perforin, along with elevated CD4⁺ and CD8⁺ T-cell signals. In vivo experiments showed that EGFR-targeted RNA-Exo-PTX effectively suppressed tumor progression and reduced PD-L1 and Ki-67 expression in tumor tissues, accompanied by upregulation of PTEN and inhibition of AKT/mTOR signaling. Blockade of EGFR weakened the antitumor effects, whereas PRELP overexpression further enhanced therapeutic efficacy. EGFR-targeted RNA-exosome composite paclitaxel nanoparticles effectively suppress colorectal cancer progression and attenuate immune evasion, highlighting their potential value in targeted chemotherapy and immunomodulatory strategies for CRC.