Small interfering RNA (
siRNA) has significant potential to evolve into a new class of
pharmaceutical inhibitors, but technologies that enable robust, tissue-specific intracellular delivery must be developed before effective clinical translation can be achieved. A pH-responsive, smart polymeric nanoparticle (SPN) with
matrix metalloproteinase (MMP)-7-dependent proximity-activated targeting (PAT) is described here. The PAT-SPN was designed to trigger cellular uptake and cytosolic delivery of
siRNA once activated by MMP-7, an
enzyme whose overexpression is a hallmark of
cancer initiation and progression. The PAT-SPN is composed of a corona-forming PEG block, an MMP-7-cleavable
peptide, a cationic
siRNA-condensing block, and a pH-responsive, endosomolytic terpolymer block that drives self-assembly and forms the PAT-SPN core. With this novel design, the PEG corona shields cellular interactions until it is cleaved in MMP-7-rich environments, shifting SPNĪ¶-potential from +5.8 to +14.4 mV and triggering a 2.5 fold increase in carrier internalization. The PAT-SPN exhibited pH-dependent membrane disruptive behavior that enabled
siRNA escape from endo-lysosomal pathways. Efficient intracellular
siRNA delivery and knockdown of the model
enzyme luciferase in R221A-Luc mammary
tumor cellssignificantly depended on MMP-7 pre-activation. These combined data indicate that the PAT-SPN provides a promising new platform for tissue-specific, proximity-activated
siRNA delivery to
MMP-rich pathological environments.