In this review, we outline examples that illustrate the design criteria for achieving macromolecular assemblies that incorporate a combination of two or more chemical, physical or biological stimuli-responsive components. Progress in both fundamental investigation into the phase transformations of these polymers in response to multiple stimuli and their utilization in a variety of pratical applications have been highlighted. Using these examples, we aim to explain the origin of employed mechanisms of stimuli responsiveness which may serve as a guideline to inspire future design of multi-stimuli responsive materials.

In this review we put the spotlight on crosslinked polymer nanogels, a promising platform that has the characteristics of an “ideal” drug delivery vehicle. Some of the key aspects of drug delivery vehicle design like stability, response to biologically relevant stimuli, passive targeting, active targeting, toxicity and ease of synthesis are discussed. We discuss several delivery systems in this light and highlight some examples of systems, which satisfy some or all of these design requirements. In particular, we point to the advantages that crosslinked polymeric systems bring to drug delivery. We review some of the synthetic methods of nanogel synthesis and conclude with the diverse applications in drug delivery where nanogels have been fruitfully employed.

Trafficking proteins inside cells is an emerging field with potential utility in basic cell biology and biological therapeutics. A robust and sustainable delivery strategy demands not only a good protection of the cargo, but also for reversibility in conjugation and activity. We report a protein-templated polymer self-assembly strategy for the formation of a sheath around the proteins and then tracelessly releasing them in the cytosol. The demonstrated versatility of the approach suggests that the strategy could be compatible with a wide array of biologics.

Supramolecular nanoassemblies, which are capable of binding and delivering either lipophilic small molecules or hydrophilic molecules, are of great interest. Concurrently binding and delivering this combination of molecules is cumbersome, because of the opposing supramolecular host requirements. We describe the development of a versatile nanoassembly system that is capable of binding and delivering both, a protein and a lipophilic small molecule, simultaneously inside the cells.

An amphiphilic nanoassembly was designed to respond to the concurrent presence of a protein and an enzyme. We present herein a system, where in the presence of these two stimuli causes a supramolecular disassembly and molecular release. This molecular release arises in the form a fluorescence response that has been shown to be specific. We also show that this system can be modified to respond only if light stimulus is also present in addition to the protein and the enzyme. Demonstration of such supramolecular disassembly principles could have wide implications in a variety of biological applications.