Harnessing pH-Sensitive Polycation Vehicles for the Efficient siRNA Delivery

pH-sensitive hydrophobic segments have been certificated to facilitate siRNA delivery efficiency of amphiphilic polycation vehicles. However, optimal design concepts for these vehicles remain unclear. Herein, by studying the library of amphiphilic polycations mPEG-PAMA(50)-P(DEA(x)-rD5A(y)) (EAE5(x/y)), we concluded a multifactor matching concept (pK a values, "proton buffering capacities" (BCs), and critical micelle concentrations (CMCs)) for polycation vehicles to improve siRNA delivery efficiency in vitro and in vivo. We identified that the stronger BCs in a pH 5.5-7.4 subset induced by EAE5(48/29) (pK, = 6.79) and EAE5(39/37) (pK(a) = 6.20) are effective for siRNA delivery in vitro. Further, the stronger BCs occurred in a narrow subset of pH 5.5-6.5 and the lower CMC attributed to higher siRNA delivery capacity of EAE5(39/37) in vivo than EAE5 48/29 after intravenous administration and subcutaneous injection. More importantly, 87.2% gene knockdown efficacy was achieved by EAE5 39/37 via subcutaneous injection, which might be useful for an mRNA vaccine adjuvant. Furthermore, EAE5(39/37) also successfully delivered siRRM2 to tumor via intravenous administration and received highly efficient antitumor activity. Taken together, the suitable pK, values, strong BCs occurred in pH 5.5-6.5, and low CMCs were probably the potential solution for designing efficient polycationic vehicles for siRNA delivery.