Tailoring liposomal spherical nucleic acid nanoparticles for biological and therapeutic potency

 描述（由申请人提供）：Toll样受体（TLR）的过度活化导致炎症性病症和疾病状态，包括致病性和无菌性，如脓毒症、自身免疫性疾病和器官移植期间的缺血再灌注损伤。该提案集中于使用新开发的携带TLR拮抗剂的脂质体球形核酸纳米颗粒（LSNA）来探测TLR免疫激活的分子机制，并推进用于潜在治疗炎症的新型治疗平台的开发。LSNA是新型纳米材料，其耐受降解，导致更高的受体结合亲和力，并且由于其3D结构和脂质核心周围的寡核苷酸排列而具有增强的效力，所述脂质核心赋予增强的生物学性质而不仅仅是其单独的组分。LSNA纳米颗粒的元素，特别是控制脂质体核心和寡核苷酸壳的化学成分，提供了一个平台，用于将靶标特异性整合到递送系统和有效载荷递送的设计中，从而允许有效抑制TLR活化。这种设计允许抑制多种但不同的受体亚型。该提案研究了双重TLR抑制性LSNA的生物学功能，其先前已被合成并验证，以抑制不同的TLR配体，其在细胞位置上不同，但共同参与组织缺血和再灌注的传播损伤。这个跨学科合作项目的中心目标是探索LSNA的化学性质，这些化学性质决定了调节下游TLR信号通路的生物学功效和特异性。目的1探索寡核苷酸骨架化学和特异性序列改变，目的是使用细胞工具（如工程化细胞系和原代人淋巴细胞）将化学组成与TLR抑制和免疫活化的效力相关联。目的2研究在体内器官移植模型中使用LSNA最小化缺血再灌注损伤的新方法。使用具有选择性抑制一种以上受体的潜力的靶向纳米颗粒是一种创新方法，因为TLR共刺激和通路串扰涉及多种疾病和病理状态。如果有效的话，将这种纳米颗粒用于治疗性应用于涉及TLR过度活性的其他炎性疾病具有广泛的可能性。

 DESCRIPTION (provided by applicant): Hyperactivation of toll-like receptors (TLRs) leads to inflammatory conditions and disease states, both pathogenic and sterile, such as sepsis, autoimmune disorders and ischemia reperfusion injury during organ transplantation. This proposal is centered on the use of a newly developed liposomal spherical nucleic acid nanoparticle (LSNA) carrying TLR antagonists to probe the molecular mechanism of immune activation by TLRs and to advance the development of a novel therapeutic platform for potential treatment of inflammation. LSNAs are novel nanomaterials that withstand degradation, lead to higher receptor binding affinities and have enhanced potency due to their 3D architecture and oligonucleotide arrangement around a lipid core that confers enhanced biological properties beyond their individual components alone. The elements of the LSNA nanoparticle, specifically the chemistry governing the liposomal core and the oligonucleotide shell, provide a platform for integrating target specificity into the design of the delivery system and payload delivery that permits potent inhibition of TLR activation. This design allows for inhibition of multiple, yet distinct, receptor subtypes. This proposal investigates the biological function of a dual TLR-inhibitory LSNA, which has been previously synthesized and validated, to inhibit distinct TLR ligands that differ in cellular location, but are jointly involved in propagating injury from tissu ischemia and reperfusion. The central goal of this transdisciplinary and collaborative project is t explore the chemical properties of LSNAs that govern biological efficacy and specificity in modulating downstream TLR signaling pathways. Aim 1 probes the oligonucleotide backbone chemistry and specific sequence alterations with the goal of correlating chemical composition with potency of TLR inhibition and immune activation using cellular tools, such as engineered cell lines and primary human lymphocytes. Aim 2 investigates novel methods to minimize ischemia reperfusion injury using LSNAs in an in vivo model of organ transplantation. The use of targeting nanoparticles with the potential to selectively inhibit more than one receptor is an innovative approach because TLR co-stimulation and pathway crosstalk is implicated in multiple diseases and pathologic states. If effective, there are widespread possibilities to applying this nanoparticle for therapeutic applications to other inflammatory diseases in which TLR hyperactivity has been implicated.