Co-delivery of Sorafenib and Anti-miR-21 via a CD44-guided Nanocarrier for Dual-pathway Inhibition in HCC Cells

Background/Aim: The clinical efficacy of sorafenib against hepatocellular carcinoma (HCC) is severely limited by limited efficacy and off-target toxicity. Overexpression of oncogenic miR-21 has been identified as a key driver of these limitations, as it downregulates the tumor suppressors PTEN and PDCD4, thereby aberrantly activating both the PI3K/Akt and STAT3 signaling pathways. To address the limitations of conventional sorafenib therapy, we aimed to construct a smart nanocarrier capable of simultaneously delivering sorafenib (SF) and anti-miR-21 specifically to HCC cells. Materials and Methods: We designed a core-shell nanoparticle consisting of a PAMAM dendrimer/anti-miR-21 polyplex core and a hyaluronic acid-sorafenib conjugate shell. This architecture enables CD44-mediated active targeting and pH-responsive drug release in the acidic tumor microenvironment. The antitumor activity of the co-delivery system was evaluated in vitro using HepG2 cells, with assessments of cell proliferation, migration, apoptosis, and the underlying signaling pathways. Results: The prepared nanoparticle exhibited potent anti-proliferative, anti-migratory, and pro-apoptotic effects in HepG2 cells. Mechanistic studies revealed that these benefits were associated with the reduced phosphorylation of key proteins in both the PI3K/Akt/mTOR and STAT3 cascades, effectively counteracting the therapy limitations that are normally fueled by miR-21 overexpression. Conclusion: Our findings demonstrate that CD44-guided co-delivery of sorafenib and anti-miR-21 provides a promising nanotherapeutic strategy to counteract therapy limitations through coordinated blockade of two major oncogenic pathways in HCC cells.