A dual-targeting graphene oxide-hyaluronic acid hybrid nanocapsule platform for stimuli-responsive synergistic cancer therapy.

Conventional chemotherapy is frequently limited by nonspecific biodistribution, inadequate intracellular delivery of hydrophobic agents, and dose-limiting toxicity to healthy tissues. Targeted and stimuli-responsive nanocarriers that enable on-demand drug release and combinational therapy have therefore attracted increasing attention for improving tumor selectivity and therapeutic outcomes. In this study, a graphene oxide-hyaluronic acid hybrid nanocapsule (FA-RGHNCs) with dual targeting properties was designed as a hydrophobic drug carrier by sonochemical method. Thiolated graphene and folic acid-modified thiolated hyaluronic acid were cross-linked through ultrasound-induced oxidation of sulfhydryl groups, resulting in the formation of disulfide bonds. The disulfide bonds serve as the structural framework of the nanocapsule shell. The core of the nanocapsules was constituted by curcumin (CUR), which was dispersed in medium-chain triglycerides. This strategy allows for the encapsulation of CUR while utilizing folic acid (FA) and hyaluronic acid (HA) as guiding agents. In addition, graphene oxide (GO) imparts photothermal properties to the system, enabling a synergistic combination of photothermal and chemotherapeutic therapies. Furthermore, disulfide bonds endow the nanocapsules with reduction/pH-responsive drug release properties in the tumor environment. Cellular uptake assays demonstrated efficient FA- and HA-mediated endocytosis of the nanocapsules by 4T1 cells. In vitro cytotoxicity assays further revealed that the combination of high CUR loading and GO-based photothermal heating generated potent synergistic chemo-photothermal antitumor effects, resulting in markedly improved tumor cell ablation. The low-cost, multifunctional, and responsive FA-RGHNCs described in this study offer a novel class of drug nanocarriers that hold great promise as tools for combined chemotherapeutic and photothermal therapy for tumors.