Designing novel multifunctional nanosystems to improve intracellular delivery

将纳米技术应用于医学的兴趣日益增长，纳米医学是由于其在药物输送、诊断和成像方面的吸引人的特性。基于纳米技术的药物输送平台（纳米颗粒，NPs）通常在1-100纳米范围内，能够在其纳米结构内封装数千种治疗和/或显像剂，并将其直接输送到疾病部位，增强其治疗效果并最大限度地减少不必要的毒性。尽管有巨大的热情和投资，但该领域尚未充分发挥其潜力，因为在欧洲和北美只有约17种纳米药物被批准用于临床使用。为了最大限度地发挥纳米技术在医疗保健中的应用潜力，需要解决一些问题，如优化纳米颗粒的生物物理化学特性，获得对纳米生物相互作用的基本理解，以及改善治疗剂的细胞内递送。我们研究计划的长期愿景是开发一个基本框架，用于合理设计和开发用于特定位点递送的NP，克服各种生物障碍以到达所需位点，确定最佳NP剂量范围以达到最大效果，并最大限度地减少纳米材料本身引起的不利影响。为此，我的研究计划主要围绕两个相互关联的主题：设计和合成先进的多功能NP平台，用于改善各种药物的细胞内递送；并探索它们与血液，组织，细胞和细胞内成分在体外和体内的相互作用。该研究计划的短期目标是详细了解氧化还原反应性NPs在细胞内运输和有效载荷传递的背景下与细胞内组分的纳米生物相互作用。我们的目标是1)开发用于核苷酸递送的新型氧化还原反应性NPs。2)研究NP与胞内溶酶体组分相互作用对生物环境下细胞内运输和递送的影响。长期目标是将从这些研究中获得的知识整合到一个反馈回路中，以开发下一代NPs。我的研究成果将为合理设计有效的纳米颗粒给药系统提供指导，从而推动纳米医学研究领域的发展。最重要的是，在这个研究项目中训练的高素质人才将学习化学、工程和生物学的各种实验和分析技能。此外，他们还将受益于强大的跨学科环境，并获得宝贵的研究经验，为他们在工业界和学术界的职业生涯做好准备。

The growing interest in applying nanotechnology to medicine, nanomedicine, is due to its appealing features in drug delivery, diagnosis, and imaging. Nanotechnology-based drug delivery platforms (nanoparticles, NPs) are typically in 1-100 nm range, capable of encapsulating thousands of therapeutic and/or imaging agents inside their nanostructures and delivering them directly to the disease sites, enhancing their therapeutic effects and minimizing unwanted toxicities. Despite significant enthusiasm and investment, the field has not yet reached its full potential, as only ~17 nanomedicines have been approved for clinical use in Europe and North America. Several issues, such as optimizing the biophysiochemical properties of NPs, gaining the fundamental understanding of nano-bio interactions, and improving the intracellular delivery of therapeutic agents, need to be addressed to maximize the potential of nanotechnology applications in healthcare. The long-term vision of our research program is to develop a fundamental framework for rationally designing and developing NPs for site-specific delivery, overcoming a variety of biological barriers to reach desired sites, identifying optimal NP dose ranges to achieve maximum effect, and minimizing adverse effects induced by the nanomaterials themselves. To this end, my research program is centred around two main interconnected themes: the design and synthesis of advanced multifunctional NP platforms for improved intracellular delivery of a variety of agents; and the exploration of their interactions with blood, tissue, cellular and intracellular components in vitro and in vivo settings. The short-term objective of the proposed research program is to gain a detailed understanding of nano-bio interactions of redox-responsive NPs with intracellular components in the context of NPs' intracellular trafficking and payload delivery. Our aims are 1) Develop novel redox-responsive NPs for nucleotides delivery. 2) Study the impact of NP's interactions with endosomal-lysosomal components on intracellular trafficking and delivery in biological settings. The long-term goal is to incorporate the knowledge gained from these studies into a feedback loop to develop next-generation NPs. The outcome of my research program will provide guidelines for rationally designing potent nanoparticle-based drug delivery systems and thus advancing the nanomedicine research field. Most importantly, highly qualified personnel trained in this research program will learn various experimental and analytical skills in chemistry, engineering, and biology. Additionally, they will also benefit from a robust interdisciplinary environment and gain valuable research experience equipping them for careers in both industry and academia.