Engineering Exosome for Pancreatic Cancer Targeting Therapies - Pancreatic Ductal Adenocarcinoma (PDAC) is one of the deadliest cancers and ranks fourth in cancer-
related deaths in the United States. Therapies for pancreatic cancer are largely hindered by the lack of an
effective delivery system. Exosomes are emerging as a promising type of nanocarrier for drug/gene delivery due
to the unique properties of these naturally derived, nanoscale extracellular vesicles and their innate ability to
shuttle proteins, lipids and DNA/RNA between cells. However, major challenges exist, including their inability to
target tumor cells and their high proportion of clearance by the mononuclear phagocyte system (MPS) of the
liver and spleen. Our long-term goal is to develop innovative nanocarriers with low immunogenicity, high
biocompatibility, increased stability, longer circulation times, and highly active tumor cell targeting. Using novel
exosomal engineering techniques, we recently found that (a) incorporation of a tumor-homing peptide (RGD)
onto exosomal surface marker CD9 (ExoCD9-RGD) results in specific binding to and uptake by integrin v3-
expressing cancer cells, and (b) exosomes overexpressing CD47, a “don’t eat me” signal, via its minimal self-
peptide (CD47p110-130), interact with signal regulatory proteins (SIRP, CD172A) on macrophages to significantly
reduce liver and spleen clearance of exosomes. These findings lead to our central hypothesis that displaying
RGD and CD47p110-130 on exosomes through CD9 engineering will permit exosomes to target PDAC in vivo while
allowing exosomes to evade MPS clearance. Toward this hypothesis, we have developed “smart exosomes” by
co-displaying RGD and CD47p110-130 on the exosome surface (ExoSmart). This results in enhanced receptor binding,
thereby increasing accumulation and cytotoxic therapeutic effects in 3D stroma-rich PDAC spheroid tumor
models. With these strong preliminary data, we propose to pursue three Specific Aims to characterize ExoSmart
and validate the application of ExoSmart in drug delivery. (1) To evaluate smart exosomes co-expressing CD9-
RGD and CD9-CD47p110-130 (ExoSmart) for exclusive active PDAC targeting therapy using human PDAC stroma-
rich 3D spheroid models, both in vitro and in vivo. (2) To validate the efficacy of ExoSmart PDAC targeting
chemotherapies in a genetically engineered mouse PDAC tumor model (KPC) and clinically relevant patient-
derived xenografted (PDX) pancreatic cancer mice models. (3) To extend ExoSmart to personalized PDAC
targeting by optimizing multiple insertion sites of CD9 and tumor-targeting peptides for optimal PDAC targeting.
Collectively, our proposed research will broadly impact the field by developing innovative nanocarriers with
optimized cargos and surfaces for precision PDAC targeting. This project holds great translational potential for
cancer therapy while providing a solid basis for future work utilizing novel peptide-engineered exosome
strategies.
