Tumor-targeted adeno associated virus-loaded complexes comprising tannic acid and phenylboronic acid-polymers for orthotopic glioblastoma therapy

Adeno-associated virus (AAV) vectors have emerged as one of the most promising viral vectors for gene therapy due to their capacity for long-term transgene expression, strong safety profile and low pathogenicity, and have been applied to the treatment of refractory cancer such as glioblastoma (GBM). However, AAV-mediated cancer gene therapy faces significant obstacles, including poor tumor targeting and neutralization by pre-existing antibodies (Abs). In this study, we developed a novel GBM-targeted AAV delivery platform, the cyclic RGD-functionalized ternary complex (cRGD-ternary complex). This complex is constructed through the self-assembly of AAV, tannic acid, and cRGD-conjugated phenylboronic acid polymers. cRGD serves as a ligand targeting α_vβ₃/α_vβ₅ integrins, which are highly expressed on GBM cells. In vitro, the cRGD-ternary complex effectively evaded neutralizing Abs due to its polymer shell and maintained high gene transduction efficiency. In an orthotopic GBM mouse model, systemic administration of cRGD-ternary complex significantly enhanced gene transduction in tumors and achieved substantial tumor suppression over 24 days. Furthermore, the cRGD-ternary complex showed therapeutic efficacy comparable to AAV alone at three-fold higher dose, with negligible hepatotoxicity. This platform successfully integrates active tumor targeting, immune evasion, and efficient gene transduction, overcoming critical limitations of AAV and showing significant potential for GBM gene therapy.