Oligonucleotides with Modified Backbones as a Strategy to Improve the Delivery of Biomolecules

核酸治疗剂和生物制剂（来自活生物体的药物）具有治疗遗传疾病的变革潜力，其无与伦比的选择性有望为以前无法实现的疾病靶点提供有效的治疗方法。然而，由于它们的高分子量和亲水性，使它们难以穿过细胞膜进入细胞内靶点，从而减缓了它们向临床的转化。因此，有效和生物相容性的递送策略被高度追捧，以加速这些药物类别的发展。DNA作为一种材料，由于其生物相容性、自动合成、精确的碱基配对字母表和完整的可寻址性，在解决这些挑战方面具有独特的优势。这些特性已经引起了具有无与伦比的精度的3D结构的合成，这些结构显示出药物递送的巨大前景，因为它们可以进入细胞，而不是大多数寡核苷酸。这表明它们的3D组织在决定它们的生物学特性方面起着重要作用。然而，需要进一步的工作来确保核酸纳米结构能够可靠地进入细胞内区室并释放其治疗潜力。取代DNA的磷酸二酯骨架是一种很有前途的策略，有可能重新定义核酸如何与细胞相互作用并内化。然而，由于合成要求，它相对未被探索。因此，可接近的骨架修饰的进一步开发及其并入3D DNA架构提供了无与伦比的机会，以同时解决理解寡核苷酸骨架修饰的知识中的根本差距，并利用其用于生物制剂和核酸治疗剂的合理递送的未释放潜力。为此，我建议成立一个小组，通过三个具体目标来探索这个主题：1。主链修饰以改善用于基因编辑的DNA纳米结构的递送2.开发自组装核酸聚两性电解质作为多功能药物递送平台3.具有匹配的寡核苷酸壳的蛋白质球形核酸用于酶治疗剂的有效递送这一新知识将在规定基于阿托伐他汀的药物递送载体的合理设计方面具有变革性，并将为将骨架修饰纳入基于核酸的纳米结构提供路线图。此外，这一研究领域拥有巨大的潜力，成功开发核酸治疗和生物制剂，这需要有效的和生物相容性的交付策略，以充分发挥其临床潜力。这一领域的进一步发展将对卫生部门具有巨大的价值，在卫生部门，为加拿大高度流行的癌症和遗传疾病开发有效的疗法是改善患者康复的限制性步骤。

Nucleic acid therapeutics and biologics (drugs derived from living organisms) hold transformative potential for the treatment of genetic diseases, where their unmatched selectivity is expected to result in effective therapies for previously unattainable disease targets. However, their translation to the clinic is slowed down by their high molecular weight and hydrophilicity, which prevent them from easily crossing cell membranes to access intracellular targets. As a result, effective and biocompatible delivery strategies are highly sought after to accelerate the development of these drug categories. DNA, as a material, is uniquely placed to address these challenges due to its biocompatibility, automated synthesis, precise base-pairing alphabet, and complete addressability. These properties have given rise to the synthesis of 3D architectures with unmatched precision that show great promise for drug delivery since they can enter cells as opposed to most oligonucleotides. This suggests their 3D organization plays a big role in dictating their biological properties. However, further work is required to ensure nucleic acid nanostructures can access intracellular compartments reliably and unleash their therapeutic potential. Replacing the phosphodiester backbone of DNA is a promising strategy that has the potential to redefine how nucleic acids interact with cells and are internalized. Yet, it has been comparatively unexplored due to synthetic requirements. Consequently, further development of accessible backbone modifications and their incorporation into 3D DNA architectures offers an unparalleled opportunity to simultaneously address a fundamental gap in knowledge in understanding oligonucleotide backbone modifications and to harness their unleveraged potential for the rational delivery of biologics and nucleic acid therapeutics. Towards this, I propose to establish a group that will explore this topic through three specific aims: 1. Backbone modifications to improve the delivery of DNA nanostructures for gene editing 2. Development of self-assembling nucleic acid polyampholytes as a versatile drug delivery platform 3. Protein spherical nucleic acids with matched oligonucleotide shells for the effective delivery of enzyme therapeutics This new knowledge will be transformative in dictating the rational design of oligonucleotide-based drug delivery vehicles and will provide a road map for incorporating backbone modifications into nucleic acid-based nanostructures. Moreover, this research area holds tremendous potential for the successful development of nucleic acid therapeutics and biologics, which require effective and biocompatible delivery strategies to reach their full clinical potential. Further developments in this area will be of tremendous value in the health sector, where the development of effective therapies for cancer and genetic diseases that are highly prevalent in Canada is the limiting step towards improving patient recovery.