Lipoplexes and polyplexes, that is, assemblies o
f cationic lipids and polymers with nucleic acids, respectively, are popular nanocarriers
for delivery o
f genes or siRNA into cells
for therapeutic or cell biological purposes. Although endocytosis represents a major mechanism
for their cellular entry, very little is known about parameters that govern early events in the initial interaction o
f such delivery devices with the cell sur
face. Here, we demonstrate that prior to entry, poly- and lipoplexes are captured by thin, actin-rich
filopodial extensions, protruding
from the cell sur
face. Subsequent additional recruitment and local clustering o
f filopodia-localized syndecans, presumably driven by multivalent interactions with the polycationic nanocarriers, appear instrumental in their processing to the cell body. Detailed microscopic analyses reveal that the latter relies on either directional sur
fing along or retraction o
f the
filopodia. By inter
fering with actin polymerization or inhibiting the motor protein myosin II, localized at the base o
f filopodia, our data reveal that the binding o
f the nanocarriers to and subsequent clustering o
f syndecans initiates actin retrograde
flow, which moves the syndecan-bound nanocarriers to the cell body. At the present experimental conditions, inhibition o
f this process inhibits nanocarrier-mediated trans
fection by 50鈥?0%. The present
findings add novel insight to our understanding o
f the mechanism o
f nanocarrier-cell sur
face interaction, which may be instrumental in
further improving delivery e
fficiency. In addition, the current experimental approach may also be o
f relevance to improving our understanding o
f cellular in
fection by viruses and pathogenic bacteria, given a striking parallel in
filopodia-mediated processing o
f these in
fectious particles and nanocarriers.
Keywords:
f="http://pubs.acs.org/action/doSearch?action=search&searchText=lipo%2Fpolyplexes&qsSearchArea=searchText">lipo/polyplexes; f="http://pubs.acs.org/action/doSearch?action=search&searchText=polycationic+nanocarriers&qsSearchArea=searchText">polycationic nanocarriers; f="http://pubs.acs.org/action/doSearch?action=search&searchText=filopodial+extensions&qsSearchArea=searchText">filopodial extensions; f="http://pubs.acs.org/action/doSearch?action=search&searchText=actin+retrograde+flow&qsSearchArea=searchText">actin retrograde flow