CAREER:Membrane-Mimicking Nanomaterials with Tunable Elasticity for Selective and Efficient Intracellular Delivery

非技术摘要：休斯顿大学材料研究部生物材料计划授予休斯顿大学的这一职业奖项是创造一种由具有可调机械性能的聚合物核心组成的脂膜，并研究所谓的纳米脂质体(NLS)的细胞识别和内化。在癌症等治疗药物旨在杀死细胞的疾病中，系统性给药可能会严重损害健康细胞，导致正在接受治疗的患者出现不希望看到的副作用。纳米脂质体是一种非常小的脂囊，可以将这些有毒药物只携带到患病细胞中，而不会损害体内的健康细胞，从而将其副作用降至最低。然而，这些携带者应该被仔细地定制，以处理受不同疾病影响的选定细胞组，同时保留其他细胞。该项目的目标是生成一个工具箱，用于设计和开发高度定制的纳米脂质体，用于携带用于广泛治疗应用的药物。这项研究的影响远远超出了生物材料和药物输送领域，因为它解决了当今医学中的一个重大挑战，即选择性和高效的药物输送，影响到数百万患有癌症或神经疾病等毁灭性疾病的患者的生活。此外，通过支持多样化的休斯敦社区中女性青年的成长和赋权，该项目将提高整个社区的生活质量。技术摘要：在迄今开发的纳米递送工具中，纳米脂质体(NLS)显示出将生物活性分子高效递送到人体特定部位的最大希望，因此，在研究实验室之外找到了应用。脂膜的一个特别吸引人的方面在于它们能够模拟生物膜的流体和动态性质。这一独特的功能可以有效地用于动态调整膜表面属性，为交付应用提供了极好的机会。然而，NLS的问题是缺乏机械稳定性和对货物释放的控制。为解决这些限制而开发的一种吸引人的策略是在NLS中添加一种能够提供机械稳定性和可控释放的固体纳米颗粒作为核心。尽管人们对这种用于运输的混合动力汽车的兴趣迅速增长，但对这些系统中结构-功能关系的基本理解仍然存在差距，阻碍了它们的充分潜力的实现。特别是，这些混合动力车辆与它们的亲本系统之间的主要区别包括：(A)在其他高度变形的NL内存在硬核，以及(B)在具有其他静态表面的固体NP上动态显示靶向部分，以及它们对这些系统性能的影响仍未被探索。这项由材料研究部生物材料计划授予休斯顿大学的职业奖项是为了填补上述空白，并提供对固体核心脂质体与其功能和细胞相互作用相关的独特物理化学方面的深入了解。为此，将开发一种具有机械可调聚合物核心的多种多样的靶向脂膜，并系统地研究其细胞识别和内化。本项目的最终目标是开发一种刺激响应性仿膜载体，同时提供高特异性、高效率、机械稳定性和可控释放的生物活性分子在细胞内的传递。这项工作具有潜在的变革性，因为它旨在开发提供机械稳定性和受控释放的纳米材料，以及细胞内治疗药物的高选择性和有效性--这是包括癌症研究和再生医学在内的几个医学和生物医学研究领域尚未满足的需求。此外，该项目是首次研究固体核心脂膜的结构-功能关系--这是一种快速增长的纳米递送材料。此外，该项目将阐明纳米生物材料的基本但尚未探索的方面：(I)核心机械硬度在NLS中的作用，以及(Ii)配体的表面迁移率在其细胞相互作用中对目标NPs的影响。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Non-Technical Abstract: This CAREER award by the Biomaterials Program in the Division of Materials Research, to the University of Houston, is to create a class of liposomal membranes that comprise a polymeric core with tunable mechanical properties, and study the cell recognition as well as internalization of the so-called nanoliposomes (NLs). In diseases like cancer where therapeutic drugs are designed to kill cells, systematic administration of drugs can severely damage healthy cells, leading to undesired side effects in patients undergoing treatment. Nanoliposomes are extremely small lipid capsules that can carry these toxic drugs only to diseased cells without harming healthy cells in the body, minimizing their side effects. These carriers should, however, be carefully tailored to address selected group of cells affected in different diseases while sparing other cells. The goal of this project is to generate a toolbox for design and development of highly tailored nanoliposomes for carrying drugs for a wide range of treatment applications. The impact of this study goes far beyond the fields of biomaterials and drug delivery as it tackles a major challenge in today's medicine, namely selective and efficient drug delivery, impacting the lives of millions of patients with devastating diseases like cancer or neurological disorders. Additionally, by supporting the growth and empowerment of female youth in the diverse Houstonian community, this project will raise the quality of life for this entire community.Technical Abstract: Among nano-delivery vehicles developed to date, nanoliposomes (NLs) have shown the greatest promise for efficient delivery of bioactive molecules to specific sites in the body and have hence, found applications beyond research laboratories. A particularly attractive aspect of liposomal membranes lies in their ability to mimic the fluid and dynamic nature of biological membranes. This unique feature can be effectively used for dynamic adjustment of membrane surface properties, presenting outstanding opportunities for delivery applications. NLs, however, suffer from the lack of mechanical stability and control over the cargo release. An appealing strategy developed to address these limitations is to add a solid nanoparticle that can provide mechanical stability and controlled release, as a core into NLs. Despite the fast growing interest in such hybrid vehicles for delivery applications, there remains a gap in fundamental understanding of structure-function relationship in these systems, hindering their full potential realization. Particularly, the key differences between these hybrid vehicles and their parental systems including (a) the presence of a stiff core within an otherwise highly deformable NL, and (b) the dynamic display of targeting moieties on a solid NP with an otherwise static surface, and their impact on the performance of these systems have remained unexplored. This CAREER award by the Biomaterials Program in the Division of Materials Research, to the University of Houston is to fill the above-mentioned gap and provide an in depth understanding of the unique physiochemical aspects of solid-core liposomes in relation to their functionality and cellular interactions. To this end, a versatile class of targeted liposomal membranes with mechanically tunable polymeric cores will be developed and systematically studied for cell recognition and internalization. The ultimate goal of this project is to develop a stimuli-responsive membrane-mimicking vehicle that can simultaneously offer high specificity, high efficiency, mechanical stability, and controlled release for intracellular delivery of bio-active molecules. This work is potentially transformative as it aims to develop nanomaterials that offer mechanical stability and controlled release along with high selectivity and efficacy for intracellular delivery of theranostics -an unmet need in several medical and biomedical research areas including cancer research and regenerative medicine. In addition, this project is the first study on the structure-function relationship in solid core liposomal membranes -a rapidly growing class of delivery nanomaterials. Moreover, this project will shed light on fundamental yet unexplored aspects of nano-scale biomaterials: (i) the role of core mechanical stiffness in NLs, and (ii) the effect of surface mobility of ligands on targeted NPs, in their cellular interactions.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.