Nanogels for biomedical applications require polymeric building blocks that show high hydrophilicity and (thermo-)responsive properties without immune response risks. Polysulfoxides offer these advantages but have not yet been translated to 3-dimensional colloidal materials. To examine their potential as alternatives to established systems, we developed a synthetic platform with synthetic control and chemical versatility. For this, we utilize the thermo-responsive properties of a polymethacrylate with propyl sulfoxide side groups, that is, poly(2-(n-propyl-sulfoxide)ethyl methacrylate) (P(nPr-SEMA)). Its phase transition near body temperature enables nanogel preparation via conventional precipitation polymerization in an all-aqueous system. To fully assess this approach's potential, we first demonstrate control over colloidal properties like size, size distribution, and crosslinking density. We examine the influence of these parameters on the temperature-dependent swelling profiles and develop a standard synthetic protocol. Second, we examine synthetic versatility to introduce additional stimuli-responsiveness. For this, we introduce methacrylic acid (MAA) as pH-responsive co-monomer and examine resulting double-sensitive swelling. Third, we add network degradability through reduction-cleavable crosslinker bis(2-methacryloyloxyethyl) disulfide (DSDMA). Fourth, we demonstrate that multi-responsive nanogels exhibit low cytotoxicity and high colloidal stability in biologically relevant media. Overall, this systematic study establishes P(nPr-SEMA)-based nanogels as versatile alternatives to established temperature-responsive nanogels for biomedical applications, for example, drug delivery.
