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.