EGFR ‐Targeted RNA –Exosome Nanoparticles Delivering Paclitaxel Suppress Colorectal Cancer via PRELP Upregulation

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.