Umrao Saurabh, Dwivedy Abhisek, Haak Payton L, Gandavadi Dhanush, Rund Laurie A, Chen Chi, Zhou Lifeng, Duan Jinwei, Fang Ying, Steelman Andrew J, Wang Xing
Department of Bioengineering, Grainger College of Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Nick Holonyak Jr. Micro and Nanotechnology Laboratory, Grainger College of Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
bioRxiv. 2025 Jul 25:2025.07.21.666049. doi: 10.1101/2025.07.21.666049.
The continued emergence of antigenic drift and drug-resistant viral strains highlights the need for antiviral strategies that deliver robust efficacy, broad subtype coverage, and minimal off-target toxicity. We demonstrate a potent and broad-spectrum strategy that employs hybrid biomaterials of Urumin (a host defense peptide) and a honeycomb (HC) DNA origami through spatially organized multivalent presentation for enhanced antiviral efficacy. Molecular dynamics simulations reveal that Urumin penetrates and destabilizes the hemagglutinin (HA) trimer core, disrupting influenza A viral (IAV) entry. Arranging Urumin in trimeric clusters on the HC enables potent multivalent binding to trimeric HAs on IAV, enhancing antiviral efficacy at nanomolar concentrations, ~1,000-fold more effective than free Urumin. In vitro assays confirm HC-Urumin outperforms free Urumin in blocking viral entry and preserving cell viability in more IAV subtypes. In vivo studies show that compared to free Urumin, HC-Urumin treatment reduces disease severity, preserves physiological behavior, and decreases mortality in infected mice, while maintaining virus-specific adaptive immune responses without altering humoral immunity. Our study offers an advanced and effective materials platform and strategy for broad-spectrum, low-dose intervention against human and animal IAVs, which can be adapted to combat other viruses by patterning corresponding host defense peptides on custom designed DNA nanostructures.
抗原性漂移和耐药性病毒株的不断出现凸显了对抗病毒策略的需求，这些策略需具备强大的疗效、广泛的亚型覆盖范围以及最小的脱靶毒性。我们展示了一种高效且广谱的策略，该策略通过空间组织的多价展示，利用乌鲁明（一种宿主防御肽）和蜂窝状（HC）DNA折纸的混合生物材料来增强抗病毒效果。分子动力学模拟表明，乌鲁明能够穿透并破坏血凝素（HA）三聚体核心，从而干扰甲型流感病毒（IAV）的进入。将乌鲁明排列在HC上的三聚体簇中，能够与IAV上的三聚体HA进行有效的多价结合，在纳摩尔浓度下增强抗病毒效果，比游离的乌鲁明有效约1000倍。体外试验证实，在阻断病毒进入以及在更多IAV亚型中保持细胞活力方面，HC - 乌鲁明优于游离的乌鲁明。体内研究表明，与游离的乌鲁明相比，HC - 乌鲁明治疗可降低疾病严重程度，保持生理行为，并降低感染小鼠的死亡率，同时维持病毒特异性适应性免疫反应而不改变体液免疫。我们的研究为针对人和动物IAV的广谱、低剂量干预提供了一个先进且有效的材料平台和策略，通过在定制设计的DNA纳米结构上构建相应的宿主防御肽，该平台和策略可适用于对抗其他病毒。
