Key Laboratory of Medical Molecular Virology of MOE/NHC/CAMS, School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity Fudan University, Shanghai 200032, China.
School of Pharmacy, Shanghai Pudong Hospital & Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
ACS Biomater Sci Eng. 2024 Jul 8;10(7):4374-4387. doi: 10.1021/acsbiomaterials.4c00749. Epub 2024 Jun 13.
DNA vaccines represent an innovative approach for the immunization of diverse diseases. However, their clinical trial outcomes are constrained by suboptimal transfection efficiency and immunogenicity. In this work, we present a universal methodology involving the codelivery of Toll-like receptor 7/8 agonists (TLR7/8a) and antigen gene using TLR7/8a-conjugated peptide-coated poly(β-amino ester) (PBAE) nanoparticles (NPs) to augment delivery efficiency and immune response. Peptide-TLR7/8a-coated PBAE NPs exhibit advantageous biophysical attributes, encompassing diminutive particle dimensions, nearly neutral ζ potential, and stability in the physiological environment. This synergistic approach not only ameliorates the stability of plasmid DNA (pDNA) and gene delivery efficacy but also facilitates subsequent antigen production. Furthermore, under optimal formulation conditions, the TLR7/8a-conjugated peptide coated PBAE NPs exhibit a potent capacity to induce robust immune responses. Collectively, this nanoparticulate gene delivery system demonstrates heightened transfection efficacy, stability, biodegradability, immunostimulatory effect, and low toxicity, making it a promising platform for the clinical advancement of DNA vaccines.
DNA 疫苗代表了一种针对多种疾病免疫接种的创新方法。然而，它们的临床试验结果受到转染效率和免疫原性不理想的限制。在这项工作中，我们提出了一种通用的方法，涉及使用 TLR7/8a 缀合肽包被的聚（β-氨基酯）（PBAE）纳米颗粒（NPs）共递送 Toll 样受体 7/8 激动剂（TLR7/8a）和抗原基因，以提高递送效率和免疫反应。肽-TLR7/8a 包被的 PBAE NPs 具有有利的物理特性，包括微小的颗粒尺寸、接近中性的 ζ 电位和在生理环境中的稳定性。这种协同方法不仅改善了质粒 DNA（pDNA）的稳定性和基因传递效率，还有助于随后的抗原产生。此外，在最佳配方条件下，TLR7/8a 缀合肽包被的 PBAE NPs 具有诱导强大免疫反应的强大能力。总的来说，这种纳米颗粒基因传递系统表现出更高的转染效率、稳定性、生物降解性、免疫刺激性和低毒性，使其成为 DNA 疫苗临床应用的有前途的平台。
