The incidence of pancreatic
neuroendocrine tumor (
PNET) has continued to rise. Due to their indolent feature,
PNET patients often present with incurable, metastatic diseases. Novel
therapies are urgently needed. We have previously shown that Receptor for
Hyaluronic Acid-Mediated Motility
isoform B (RHAMMB) and Bcl-xL are upregulated in
PNETs and both of them promote
PNET metastasis. Because
RHAMM protein is undetectable in most adult tissues, we hypothesized that RHAMMB could be a gateway for nanomedicine delivery into
PNETs. To test this, we developed a RHAMMB-targeting nanoparticle (NP). Inside this NP, we assembled
small interfering RNA (
siRNA) against Bcl-xL (siBcl-xL) and mitochondria-fusing
peptide KLA. We demonstrated that RHAMMB-positive
PNETs picked up the RHAMMB-targeting NPs. siBcl-xL or KLA alone killed only 30% of
PNET cells. In contrast, a synergistic killing effect was achieved with the co-delivery of siBcl-xL and
KLA peptide in vitro. Unexpectedly, siBcl-xL induced cell death before reducing
Bcl-xL protein levels. The systemically injected RHAMMB-targeting NPs carrying siBcl-xL and
KLA peptide significantly reduced
tumor burden in mice bearing RHAMMB-positive
PNETs. Together, these findings indicate that the RHAMMB-targeting nanotherapy serves as a promising drug delivery system for
PNET and possibly other
malignancies with upregulated RHAMMB. The combination of siBcl-xL and
KLA peptide can be a
therapy for
PNET treatment.