Abstract
BACKGROUND: Hepatocellular carcinoma (HCC) is associated with one of the highest cancer-related mortality rates worldwide and remains therapeutically challenging. There is an urgent need for innovative treatment strategies. Although Newcastle disease virus (NDV) has demonstrated potent oncolytic activity in vitro and in animal models, free virions administered intravenously are rapidly neutralized by pre-existing antibodies and exhibit poor tumor tropism, significantly limiting their clinical translation (Shalhout et al., Nat Rev Clin Oncol 20(3):160-177, 2023). OBJECTIVES: This study aimed to develop porous gelatin methacrylate (GelMA) microneedles (MNs) for encapsulating Newcastle disease virus (NDV) and to evaluate their antitumor efficacy against HCC. METHODS: GelMA microneedles were fabricated and screened across a concentration gradient for biocompatibility and degradability. The optimal NDV-loaded formulation was subsequently evaluated for safety and therapeutic efficacy in HCC models using in vitro assays and a subcutaneous HCC xenograft model in nude mice. RESULTS: Microneedles prepared with 10% (w/v) GelMA exhibited excellent biocompatibility and degradability. 10% GelMA MNs loaded with an NDV-gelatin mixture sustained NDV release for over 24 h. Compared with the free virus, they induced significantly stronger inhibition of proliferation, migration, and invasion, and promoted greater apoptosis in HCC cells. In mice bearing subcutaneous HCC xenografts, NDV encapsulated in 10% GelMA MNs markedly suppressed tumor growth without significant changes in body weight or histological damage to major organs. Histological analysis further confirmed reduced proliferation and increased apoptosis in the treated group. CONCLUSION: GelMA-encapsulated NDV microneedles represent a novel, promising and well-tolerated therapeutic strategy for HCC.