Phospholipid-Decorated Glycogen Nanoparticles for Stimuli-Responsive Drug Release and Synergetic Chemophotothermal Therapy of Hepatocellular Carcinoma

Dendritic macromolecules are potential candidates for nanomedical application. Herein, glycogen, the natural hyperbranched polysaccharide with favorable biocompatibility, is explored as an effective drug vehicle for treating liver cancer. In this system, glycogen is oxidized and conjugated with cancer drugs through a disulfide link, followed by in situ loading of polypyrrole nanoparticles and then coated with functional phospholipids to form the desired system, Gly-ss-DOX@ppy@Lipid-RGD. The phospholipid layer has good cell affinity and can assist the system to penetrate into cells smoothly. Additionally, combined with the "fusion targeting" of glycogen and the active targeting effect of RGD toward liver cancer cells, Gly-ss-DOX@ppy@Lipid-RGD presents efficient specificity and enrichment of hepatocellular carcinoma. Owing to the glutathione-triggered cleavage of disulfide linkers, Gly-ss-DOX@ppy@Lipid-RGD can controllably release drugs to induce cell nucleus damage. Meanwhile, the polypyrrole nanoparticles can absorb near-infrared light and radiate heat energy within tumors. Besides enhancing drug release, the heat can also provide photothermal treatment for tumors. As proved by in vitro and in vivo experiments, Gly-ss-DOX@ppy@Lipid-RGD is a remarkable candidate for synergistic chemophotothermal therapy with high anticancer therapeutic activity and reduced systematic toxicity, efficiently suppressing tumor growth. All results demonstrate that glycogen nanoparticles are expected to be a new building block for accurate hepatocellular carcinoma treatment.