Next-Generation Biomimetic Nanomedicines

癌症和神经退行性疾病是主要的全球健康问题，据估计，到2025年，每年将分别诊断出近2000万和1000万新的癌症和痴呆症病例（由神经退行性疾病引起）。目前的靶向治疗方法包括通过抑制特定疾病促进蛋白质的功能来发挥作用的小分子和抗体。这些药物通常由于生物利用度低（到达所需作用部位的能力）和导致毒性的脱靶效应而使用有限。此外，疾病细胞通常通过获得靶蛋白中的突变来对这些药物产生耐药性，这些突变使它们能够逃避抑制剂的作用。药物的纳米颗粒制剂，称为“纳米治疗剂”，可以帮助提高生物利用度和降低毒性。然而，由于相对于其制剂的高成本，它们的治疗改进有限，因此迄今为止尚未在临床中广泛使用。在这里，我们将通过结合我们在蛋白质工程和生物纳米技术方面的专业知识来解决这些挑战，以构建“基于纳米颗粒的目标消除器”（NTEs），旨在安全有效地破坏病理靶蛋白。靶点降解是不可逆的，因此应比靶点抑制更有效和更持久。NTE将通过用两类配体功能化纳米颗粒的表面来构建，一种用于结合感兴趣的病理靶蛋白，另一种用于结合降解效应物以选择细胞的质量控制机制-泛素-蛋白酶体系统和自噬-溶酶体系统-并驱动靶破坏。通过将目标和降解效应物浓缩在这些纳米颗粒“反应器”的小体积内，我们应该大大加速它们之间的反应。NTE平台的一个关键优势是它将能够利用各种不同的结合配体（小分子、肽、寡核苷酸），从而可以应用于潜在的任何靶点，并可以利用许多不同的降解途径。许多疾病驱动因素很难通过常规手段给药，因为它们不是酶或受体，其活性可以直接用小分子配体阻断;这些驱动因素将适用于我们的NTE平台。我们还将开发刺激响应性NTE，可以远程激活，并以特定的方式，使治疗更安全。这项工作必然是跨学科的。通过研究人员和我们的合作者之间的互动，该项目将汇集纳米生物技术，化学，生物化学以及细胞和癌症生物学方面的专业知识，长期目标是以有效和相关的方式翻译工作。这些结果将为细胞质量控制途径的基本分子机制提供新的见解，并将提供一种新的方法来靶向蛋白质进行破坏。我们将重点关注癌症和神经退行性疾病靶点，但NTE平台可以广泛应用于许多其他疾病领域。这些结果还将为更广泛地利用这些下一代仿生纳米药物作为具有靶向蛋白质降解以外的多种活性的邻近诱导药物提供概念证明。

Cancer and neurodegenerative diseases are major global health problems, and it is estimated that by 2025 nearly 20 million and 10 million new cases of cancer and dementia (caused by neurodegenerative diseases), respectively, will be diagnosed each year. Current targeted therapeutic approaches include small molecules and antibodies that act by inhibiting the function of specific disease-promoting proteins. These drugs are often of limited use because of low bioavailability (the ability to reach the required site of action) and off-target effects that cause toxicity. Moreover, disease cells commonly develop resistance to such drugs by acquiring mutations in the target protein that allow them to escape the inhibitor's action. Nanoparticle formulations of drugs, referred to as "nanotherapeutics", can help to improve bioavailability and reduce toxicity. However, they have not been extensively used in the clinic to date because of the limited therapeutic improvements relative to the high cost of their formulation. Here we will address these challenges by combining our expertise in protein engineering and bionanotechnology to build "nanoparticle-based target eliminators" (NTEs) designed to safely and effectively destroy pathological target proteins. Target degradation is irreversible and should therefore be more effective and longer lasting than target inhibition. The NTEs will be built by functionalizing the surface of nanoparticles with two classes of ligands, one to bind a pathological target protein of interest and one to bind to degradation effectors to co-opt the cell's quality control machineries - the ubiquitin-proteasome system and the autophagy-lysosome system - and drive target destruction. By condensing targets and degradation effectors within a small volume in these nanoparticle "reactors" we should dramatically accelerate the reaction between them. A key strength of the NTE platform is that it will be able to utilise a variety of different binding ligands (small molecules, peptides, oligonucleotides) and can thereby be applied to potentially any target and can harness many different degradation pathways. Many disease drivers are hard to drug by conventional means because they are not enzymes or receptors whose activities can be straightforwardly blocked with a small-molecule ligand; these drivers will be amenable to our NTE platform. We will also develop stimuli-responsive NTEs that can be activated remotely and in a site-specific manner, making the therapy safer. This work is necessarily interdisciplinary. Through interaction between the Investigators and our collaborators, the project will bring together expertise in nano-biotechnology, chemistry, biochemistry and cell and cancer biology, with the longer-term goal of translating the work in an efficient and relevant manner. The results will provide new insights into the basic molecular mechanisms underpinning the quality control pathways of the cell and will deliver a new way to target proteins for destruction. We will focus here on cancer and neurodegenerative disease targets, but the NTE platform could be applied very widely to many other disease areas. The results will also provide proof of concept for the broader exploitation of these next-generation biomimetic nanomedicines as proximity-inducing drugs with diverse activities beyond targeted protein degradation.