N‑Cadherin
Targeted Melanin Nanoparticles Reverse
the Endothelial–Mesenchymal Transition in Vascular Endothelial
Cells to Potentially Slow the Progression of Atherosclerosis and Cancer
posted on 2024-03-01, 19:09authored byJinyuan Liu, Xiao Yu, Annaliese Braucht, Steve Smith, Congzhou Wang
Endothelial–mesenchymal transition (EndoMT) of
vascular
endothelial cells has recently been considered as a key player in
the early progression of a variety of vascular and nonvascular diseases,
including atherosclerosis, cancer, and organ fibrosis. However, current
strategies attempting to identify pharmacological inhibitors to block
the regulatory pathways of EndoMT suffer from poor selectivity, unwanted
side effects, and a heterogeneous response from endothelial cells
with different origins. Furthermore, EndoMT inhibitors focus on preventing
EndoMT, leaving the endothelial cells that have already undergone
EndoMT unresolved. Here, we report the design of a simple but powerful
nanoparticle system (i.e., N-cadherin targeted melanin nanoparticles)
to convert cytokine-activated, mesenchymal-like endothelial cells
back to their original endothelial phenotype. We term this process
“Reversed EndoMT” (R-EndoMT). R-EndoMT allows the impaired
endothelial barriers to recover their quiescence and intactness, with
significantly reduced leukocyte and cancer cell adhesion and transmigration,
which could potentially stop atheromatous plaque formation and cancer
metastasis in the early stages. R-EndoMT is achieved on different
endothelial cell types originating from arteries, veins, and capillaries,
independent of activating cytokines. We reveal that N-cadherin targeted
melanin nanoparticles reverse EndoMT by downregulating an N-cadherin
dependent RhoA activation pathway. Overall, this approach offers a
different prospect to treat multiple EndoMT-associated diseases by
designing nanoparticles to reverse the phenotypical transition of
endothelial cells.