Multiscale approaches to engineering living cells for nanotherapeutic delivery

点击翻译按钮获取中文摘要

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.