Methacrylated Carrageenan/Gelatin Interpenetrating Network Microspheres Loaded with Targeted Drugs and combined with PD-L1 Inhibitors for Hepatocellular Carcinoma Treatment

Hepatocellular carcinoma (HCC) is a highly fatal malignant tumor. The clinical outcomes of vascular interventional therapy for HCC based on existing drug-eluting microspheres remain unsatisfactory. This study adopted a unique fabrication method to synthesize methacrylated carrageenan/gelatin hydrogel embolic microspheres (MCGs). The interpenetrating network formed by these two biocompatible and absorbable natural macromolecules endows MCGs with outstanding mechanical properties and vascular conformity. MCGs could be delivered through microcatheters smoothly, and they are provided in various sizes to accommodate different clinical requirements. Their in vivo degradation behavior is controlled and predictable. Due to the strong anionic nature of carrageenan, MCGs can efficiently load and sustainably release Lenvatinib, achieving the precise delivery of this antiangiogenic targeted drug in the tumor region. Animal models reveal that the microspheres block blood vessels effectively and MCGs allow for high-dose Lenvatinib to have prolonged contact with HCC. We also propose an HCC treatment strategy by combining PD-L1 inhibitors with MCGs carrying Lenvatinib. This combination therapy is safe and effective, and the additive and synergistic effects showed impressive antitumor potency and great clinical application potential.