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的这项职业奖旨在创建一类脂质体膜，该膜包含具有可调机械性能的聚合物核心，并研究细胞识别以及所谓的纳米脂质体（NL）的内化。 在像癌症这样的疾病中，治疗药物被设计为杀死细胞，药物的系统给药可能严重损害健康细胞，导致接受治疗的患者出现不良副作用。纳米脂质体是非常小的脂质胶囊，可以将这些有毒药物仅携带到患病细胞，而不会伤害体内的健康细胞，从而最大限度地减少其副作用。然而，这些载体应该仔细定制，以解决在不同疾病中受影响的选定细胞群，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，用于携带药物用于广泛的治疗应用。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的一个重大挑战，即选择性和有效的药物输送，影响了数百万患有癌症或神经系统疾病等毁灭性疾病的患者的生活。此外，通过支持在不同的休斯顿社区的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：在迄今为止开发的纳米递送载体中，纳米脂质体（NLs）已显示出最大的希望，可将生物活性分子有效递送到身体的特定部位，因此，发现了研究实验室之外的应用。脂质体膜的一个特别有吸引力的方面在于它们模仿生物膜的流体和动态性质的能力。这种独特的功能可以有效地用于膜表面特性的动态调节，为输送应用提供了出色的机会。然而，NL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有吸引力的策略是将可以提供机械稳定性和受控释放的固体纳米颗粒作为核添加到NL中。尽管人们对这种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，阻碍了它们的充分实现。特别地，这些混合载体和它们的亲本系统之间的关键差异包括（a）在另外高度可变形的NL内存在刚性核，和（B）靶向部分在具有另外静态表面的固体NP上的动态展示，以及它们对这些系统的性能的影响仍然未被探索。休斯顿大学材料研究部生物材料项目的职业生涯奖旨在填补上述空白，并深入了解固体核心脂质体与其功能和细胞相互作用相关的独特理化方面。为此，将开发和系统研究具有机械可调聚合物核的多功能靶向脂质体膜，用于细胞识别和内化。该项目的最终目标是开发一种刺激响应性膜模拟载体，该载体可以同时提供高特异性，高效率，机械稳定性和生物活性分子的细胞内递送的控制释放。这项工作是潜在的变革，因为它旨在开发纳米材料，提供机械稳定性和控制释放沿着高选择性和疗效的细胞内交付的治疗诊断-一个未满足的需求，在几个医学和生物医学研究领域，包括癌症研究和再生医学。此外，该项目是第一个研究固体核心脂质体膜的结构-功能关系-一种快速增长的递送纳米材料。此外，该项目将揭示纳米尺度生物材料的基本但未探索的方面：（i）核机械刚度在NLs中的作用，以及（ii）配体表面流动性对靶向NPs的影响，在其细胞相互作用中。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估来支持。

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.