Folic acid/3-carboxyphenylboronic acid dual-functionalized cellulose nanocrystals as a pH-responsive nanocarrier for improved curcumin delivery against hepatocellular carcinoma

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide due to late diagnosis, high metastasis, and poor therapeutic outcomes. Curcumin (Cur), a natural polyphenol with potent antitumor activity, is severely limited in clinical application by poor water solubility, low bioavailability, and insufficient tumor-targeting capability. Herein, a dual-targeted pH-responsive nanocarrier based on cellulose nanocrystals (CNCs) co-functionalized with folic acid (FA) and 3-carboxyphenylboronic acid (CA) was fabricated for enhanced Cur delivery to HCC cells. CNCs were aminated via silane coupling, followed by covalent co-grafting of FA and CA to obtain ACNCs@FA- CA. FA enabled targeting of folate receptors overexpressed on HCC cells, while CA played a dual role by reversibly binding Cur through boronate ester formation and recognizing sialic acid-rich tumor cell membranes. Cur was loaded with an efficiency of 13.90 ± 2.00% and exhibited pH-responsive release, reaching 81.61 ± 1.60% at pH 5.4 and 26.29 ± 1.47% at pH 7.2. In vitro studies demonstrated that Cur-loaded ACNCs@FA-CA significantly enhanced intracellular drug accumulation and cytotoxicity in HepG2 cells, with improved growth inhibition in a 3D hepatoma spheroid model. Collectively, this dual-targeted pH-responsive nanoplatform offers a promising strategy to improve the anti-HCC efficacy of Cur.