Engineered Zwitterionic Diblock Copolymer‐siRNA Polyplexes Provide Highly Effective Treatment of Triple‐Negative Breast Cancer in a 4T1 Murine Model

Abstract Self‐assembly of small interfering RNA (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 are 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 −1 . 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.