Multiscale approaches to engineering living cells for nanotherapeutic delivery

项目总结 将药物包裹在纳米粒子中的纳米粒子疗法(NTS)已成为一种初级技术 治疗多种疾病的治疗方法。纳米管包含多种纳米颗粒类型，并且可以 轻松整合多种药物，从小分子到大分子，再到生物制品。这个 纳米粒子和微囊化药物的多样性使NTS成为一种多功能的治疗方式 临床研究用于治疗各种组织中的多种疾病。就像任何其他治疗方式一样， NTS的成功应用需要将其特定的递送到目标位置，同时避免目标外的积累。 然而，由于其独特的特征(例如，大尺寸)，NTS面临着独特的生物障碍，这导致其 不利的药代动力学(PK)、生物分布和药效学(PD)资料。因此，一个紧迫的问题 而尚未解决的挑战是更好地了解非关税壁垒的生物障碍，并制定有效的 指导NTS精确投放的策略，以充分释放其治疗潜力。为此， 我的研究计划的总体目标是确定NTS的理想输送参数并开发新的 战略是精确交付NTS的战略。我们关注的一个策略是利用来自内在的灵感 生物学，特别是活细胞。事实上，活细胞，如循环细胞，可以作为理想的递送细胞。 系统。循环细胞可以在体内导航，感知病理信号，并通过 一种积极的运输机制。NTS可被负载到循环细胞内或表面以被 送到目标地点。我的研究在这一领域取得了重大进展，我们开发了小说 方法将NTS与不同的活细胞结合，证明两种循环细胞(红细胞 和巨噬细胞)可调节NTS的PK、生物分布和疗效。在中国的快速发展 推动细胞向NTS递送突出了迫切需要机制研究以i)阐明如何 活细胞载体和NTS之间的界面影响NTS的运输和载体细胞的迁移 确定利用活细胞精确运送NTS的原则。我们的目标是利用我们的专业知识在 纳米颗粒设计和细胞工程，以解决这一未得到满足的需求。具体地说，在未来五年，使用 以各种组织中发生的炎症为模型，我们将重点放在：1)了解基于细胞的载体如何 影响NTS给药结果，II)研究NTS的负载量和物理化学性质 影响载体细胞的迁移，以及iii)开发多尺度策略以实现细胞特异性的递送 NTS。这些研究将使我们能够建立一套管理交付效率和 NTS与活细胞的相互作用，最终将提高NTS的能力并拓宽NTS的光谱 用于治疗各种疾病。我们项目的成功实现不仅将有助于理解 NTS与活细胞相互作用的关键特征，但也为Rational工程开发了一套原则 活细胞，以改善NTS和其他疗法的生物学结果。

PROJECT SUMMARY Nanoparticle therapeutics (NTs) that encapsulate drugs in a nanoscale particle has emerged as a primising therapeutic modality for treating many diseases. NTs encompass a diverse array of nanoparticle types and can easily incorporate a wide-array of drugs, ranging from small molecules, to macromolecules, to biologics. The diversity of nanoparticles and encapsulated drugs renders NTs a versatile therapeutic modality that is being clincally investigated to treat many dieseases in various tissues. Like any other therapetic modality, the successful application of NTs requires their specific delivery to target sites while avoiding off-target accumulation. However, owing to their distinct features (e.g. large-size), NTs face unique biological barriers which lead to their unfavorable pharmacokinetics (PK), biodistribution, and pharmacodynamics (PD) profiles. As such, a pressing and unaddressed challenge is to better understand the biological barriers for NTs and to develop effective strategies to guide the precise delivery of NTs to unleash their full therapeutic potential. Toward this end, the overarching goal of my research program is to identify ideal delivery parameters for NTs and to develop novel strategeis for precise delivery of NTs. One strategy we are focusing on is to utilize inspirations from the intrinsic biology, living cells in particular. Indeed, living cells such as circulatory cells can be leveraged as ideal delivery systems. Circulatory cells can navigate the body, sense pathological signals, and reach diseased tissues via an active transport mechanism. NTs can be loaded inside or onto the surface of circulatory cells to be delivered to target sites. My research has made significant strides in this area where we have developed novel methods to incorporate NTs with diverse living cells and demonstrated that two circulatory cells (erythrocytes and macrophages) could modulate the PK, biodistribution, and efficacy of NTs. The rapid progression in advancing cells towards NTs delivery highlights the urgent need for mechanistic studies to i) elucidate how the interface between living cell carriers and NTs impacts the transport of NTs and migration of carrier cells and ii) to identify principles for utilizing living cells for precise delivery of NTs. We aim to capitalize our expertise in nanoparticle design and cell engineering to address this unmet need. Specifically, over the next five years, using inflammation that occurs in various tissues as a model, we will focus on i) understanding how cell-based carriers impact the outcomes of NTs delivery, ii) studying how the loading and physicochemical properties of NTs influence the carrier cells’ migration, and iii) developing multiscale strategies to achieve cell-specific delivery of NTs. These studies will enable us to establish a set of design rules that govern the delivery efficacy and interactions of NTs with living cells, which will ultimately improve the capability and broaden the spectrum of NTs for treating various diseases. Successful realization of our program will not only contribute to understanding the key features for a NTs to interact with the living cells but also develop a set of principles for rational engineering living cells to improve the biological outcomes of NTs and other therapeutics.