Chrysanthemum-like nanodrug assembled from hyaluronan-doxorubicin/cisplatin conjugate for targeted synergistic chemotherapy of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is usually diagnosed at advanced stages and has a high mortality rate and a short survival time, posing significant threats to human life and health. Chemotherapy remains the cornerstone of HCC treatment, but it still faces significant challenges of limited monotherapy efficacy and drug resistance. Herein, a stimulus-responsive hyaluronic acid (HA)-based dual-drug conjugate was proposed for efficient targeted synergistic chemotherapy of HCC. The amphiphilic conjugate (HDC) was synthesized by successively grafting doxorubicin (DOX) and cisplatin (CDDP) onto hydrazide HA (HHA) through labile hydrazone and coordination bonds, respectively. The resulting conjugate could self-assemble into well-dispersed chrysanthemum-like HDC nanoparticles with a hydrodynamic size of approximately 180 nm and a high drug content exceeding 30%. The HDC nanoparticles exhibited pH/glutathione dual-responsive drug release behaviors, effective tumor targeting via CD44 receptors-mediated endocytosis, and synergistic cancer cell-killing efficacy compared to equivalent-dose monotherapies. In vivo studies demonstrated remarkable tumor suppression and favorable biosafety. Overall, this work proposes a novel strategy that combines targeted co-delivery of DOX and CDDP with the ability to eliminate glutathione-mediated drug resistance, showing promising potential for clinical translation in HCC therapy.