Virus-Like Particle-Based Personalized Neoantigen Nano-Vaccine for Tumor Immunotherapy and Recurrence Prevention.

High recurrence rates following hepatocellular carcinoma (HCC) resection remain a significant challenge, limiting the long-term prognosis of patients. Personalized antigen vaccines have emerged as a promising strategy to reduce postoperative recurrence; however, their prolonged synthesis timelines and the inherently weak immunogenicity of personalized antigens restrict their clinical applicability. To address this issue, a Plug-and-Display system was herein utilized to display "catcher" peptides, containing autocatalytic center sequences, in the major immunodominant region (MIR) of hepatitis B core protein virus-like particles (HBc VLPs), thereby engineering a universal HBc-C platform. Simultaneously, short 15-amino-acid peptide sequences containing another segment of the autocatalytic center were used to label three HCC neoantigens. The interaction between the label and the "catcher" peptides restores the functionality of the self-catalytic core, forming stable amide bonds between them and enabling the successful construction of a nanovaccine, designated HBc-MWK. In vitro assays demonstrated that HBc-MWK significantly promotes the maturation of 68.68 ± 2.51% of dendritic cells (DCs), enhances T cell activation, and induces the secretion of cytokines such as IFN-γ and GM-CSF. In xenograft tumor models, HBc-MWK markedly enhanced the intratumoral infiltration of both CD4+ and CD8+ T cells, achieving a tumor suppression rate of 97.08 ± 2.07%. In both subcutaneous and orthotopic tumor recurrence models, HBc-MWK effectively inhibited 80% of tumor recurrence and led to the establishment of long-lasting immune memory. The strategy for constructing HBc-MWK offers an effective approach to the rapid development of highly efficient personalized tumor vaccines.