The stability of encapsulation in self-assembly systems is limited during blood circulation because of a requisite concentration for assembly formation. For deliberate molecular design for stable encapsulation, targeting, and triggered release, we have developed a facile synthetic method for highly stable, polymeric nanogels using a simple intra/interchain cross-linking reaction. We show a simple, emulsion-free method for the preparation of biocompatible nanogels that provides the ability to encapsulate hydrophobic guest molecules and surface functionalization which has potential for targeted delivery. We show that the noncovalently encapsulated guest molecules can be released in response to a biologically relevant stimulus.