An Exploratory Study on the Targeted Delivery of p53 Using the Engineered Attenuated Salmonella Strain VNP20009 for the Treatment of Glioblastoma

Source abstract

Background: Glioblastoma (GBM) is a highly aggressive malignancy with limited therapeutic options, partly because of its infiltrative growth and the difficulty of delivering therapeutics to tumor tissue. The attenuated Salmonella strain VNP20009 exhibits preferential tumor colonization and has potential as a vector for intratumoral delivery of therapeutic agents. In this study, we engineered VNP20009 to deliver the tumor suppressor protein p53 for GBM therapy. Materials and Methods: A genetic construct comprising the prpsM promoter, the SopE secretion signal, and the TP53 gene was introduced into VNP20009. The morphology, growth kinetics, and transcriptional characteristics of the engineered strain were evaluated. Intracellular p53 delivery, cell proliferation, and apoptosis were assessed in GBM cells. Antitumor efficacy, bacterial biodistribution, and biosafety were further evaluated in mice bearing subcutaneous GBM xenografts. Results: The engineered VNP20009 strain retained morphological and growth characteristics comparable to those of the VNP20009-Vector control and was capable of expressing and delivering p53. Treatment with the engineered bacteria upregulated p21 and was associated with activation of p53-related signaling in GBM cells, inhibited cell proliferation, and induced apoptosis. In vivo, the engineered bacteria preferentially accumulated in tumor tissues, enhanced intratumoral p53 expression, and significantly inhibited tumor growth. Only low bacterial burdens were detected in major organs, and preliminary histopathological safety findings revealed mild hepatic changes. Conclusions: This study developed an engineered VNP20009-based strategy for targeted delivery of p53 to GBM. By combining the intrinsic tumor tropism of VNP20009 with localized p53 delivery, this approach achieved significant antitumor activity while maintaining a favorable biosafety profile. These findings support further development of bacteria-mediated protein delivery as a potential therapeutic strategy for GBM.