Abstract:Polymer nanogels are nanosized crosslinked polymer networks, which have stable three-dimensional (3D) structures, high drug-loading efficiencies, stimuli-responsiveness, and so forth. They are part of the most promising nanoplatforms that find enormous applications in biomedicine fields, such as drug delivery, gene therapy, and bioimaging. Compared with other polymer-based nanogels, polypeptide nanogels have gained wide attention in this area due to excellent properties, such as great biocompatibility, fine stability, and nontoxicity of degradation products. Furthermore, the properties can be easily adjusted by alteration of side groups of the polypeptides using ester exchange, “click”, aminolysis or other chemical reactions. There are two common routes for the preparation of polypeptide nanogels. (i) Crosslinking of the polypeptides prepared by polymerization of amino acid N-carboxyanhydride (NCA) with monofunctional NCA group using cross-linking agent. (ii) Polymerization of amino acid NCA with difunctional NCA groups. However, traditional polypeptide nanogels fail to meet the requirements of an appropriate drug delivery platform. For example, the drug molecules cannot remain stable in the nanocarrier during circulation until arriving at the target area. Therefore, stimuli-responsive polypeptide nanogels have been developed to improve the stability during circulation and also achieve controllable drug release. The stimuli-responsive polypeptide nanogels have the ability of responding to endogenous (e.g., reduction, reactive oxygen species (ROS), pH, and enzymes) or exogenous stimuli (e.g., light and temperature). In this manner, controllable drug delivery can be realized through appropriate physical or chemical transitions of polypeptide nanogels, e.g., shrinking, swelling, or disassembly. As controlled drug release system continues to be a desired function, functional polypeptide nanogels play an important role in the advances of nanomedicines. In this feature article, a comprehensive introduction of the preparation, and applications of diverse stimuli-responsive polypeptide nanogels has been illustrated. The challenges regarding polypeptide nanogels applications are given and potential opportunities in solving them are also predicted.