Rational Design of Cationic Nanogels with Serum Tolerance for Efficient siRNA Delivery and Antitumor Therapy

Cationic polymers have been applied widely for siRNA delivery, yet most of the conventional linear or branched polymers make RNA polyplexes with poor serum stability and low delivery efficacy. We here propose cationic nanogels as a better alternative, and demonstrate their advantages for siRNA delivery. Firstly, nanogels offer a stable 3D structure which can bind RNA in different ways (surface and inside). Depending on the mixing ratio (N/P), siRNA-loaded particles respond differently to serum proteins: at high N/P (excess nanogel) siRNA is bound on interior sites and then better protected against competing serum proteins, so that delivery and transfection are efficient. Moreover, the synthetic protocol (electrostatic-templated polymerization, ETP) allows fine-tuning of the nanogels physicochemical properties (chemical composition, size and cross-linking degree etc.), so that we can systematically explore structure-performance relationships for nanogel-mediated siRNA delivery. Doing so, we find that the best delivery vehicle is a 107 nm PVBTMA (poly vinylbenzyl trimethylammonium chloride) nanogel with 5% cross-linking degree. We show that this nanogel, when loaded with siPLK1 (a tumor-specific gene silencer) achieves superior gene silencing in vitro, and an inhibition of tumor growth in vivo. Our results demonstrate clear advantages of cationic nanogels as carriers for siRNA therapeutics.