Therapeutic
recombinant proteins have numerous advantages and benefits over chemical drugs, particularly high specificity and good biocompatibility. However, the therapeutic potential and clinical application of current anticancer
protein drugs are limited as most
biomarkers are located within cells, and multiple physiological barriers exist between the point of administration and the intracellular
biomarker. Herein, we report a novel strategy to accurately deliver a cell-permeable dominant-negative TATm-
Survivin (
TmSm)
protein (T34A) to intracellular
survivin in
cancer cells by overcoming multiple barriers in vivo. A
poly(d,l-lactide-co-glycolide) (PLGA) inner core, a
polyethylene glycol (PEG) modification, and a TATm
peptide were simultaneously introduced to mediate
tumor tissue targeting and response to pH-triggered
TmSm release. Compared to free
TmSm, the PEGylated-PLGA nanoparticle platform achieved a significantly higher cellular uptake efficiency (1.79-fold for A549 and 1.77-fold for Capan-2), effectively decreased IC50 (1.22-fold for A549 and 1.17-fold for Capan-2), and largely elevated apoptosis in different
cancer cells (1.17-fold for A549 and 1.15-fold for Capan-2). Besides, this newly developed nanoplatform showed increased
protein drug accumulation in the
tumor site in A549-bearing nude mice and reached a
tumor inhibition rate of 55.81% (1.35-fold versus free
TmSm) by reducing the expression of intracellular
survivin. All these results confirmed that our newly developed delivery strategy is a very promising tool, which helps
protein drugs to cross multiple barriers in vivo and achieves precise targeting to intracellular
biomarkers. This strategy could also be applied to other types of
protein drugs to further improve their clinical anticancer therapeutic efficacy.