Engineered zwitterionic diblock copolymer-siRNA polyplexes provide highly effective treatment of triple-negative...

Self-assembly of siRNA with a block copolymer featuring guanidinium and zwitterion functionalized blocks generates core-shell-like nanovectors that provide cytosolic access to siRNA and efficiently evade phagocytic clearance. The guanidinium-functionalized inner block complexes siRNA in the nanovector interior and enables cytosolic delivery. The zwitterionic outer block provides a non-interacting shell on the nanovectors that reduces macrophage uptake in vitro and phagocytic clearance and enhances tumor localization in vivo. These nanovectors were used to treat a 4T1 (murine) model of triple-negative breast cancer (TNBC). The nanovectors deliver siRNA efficiently to 4T1 triple-negative breast cancer cells in vitro, with high selectivity relative to macrophages. This efficiency and selectivity translate into in vivo efficacy: diblock nanovectors evaded phagocytic clearance and efficiently localized in an aggressive murine 4T1 orthotopic model, with a ~3-fold increase of vector residing in the tumor compared to the homopolymer nanovectors. This increased localization efficiently knocked down STAT3 (~80%) and provided tumorostasis (100% growth inhibition) at a low dose of 0.14 mg/kg. The in vitro and in vivo efficacy of these nanovectors demonstrate the potential of engineered polymer architectures to generate effective self-assembled siRNA therapeutics that avoid phagocytic clearance for the treatment of diseases requiring systemic administration.