Elastin‐like polypeptides (ELPs) are thermally responsive biopolymers that consist of a repeated amino acid motif derived from human tropoelastin. These peptides exhibit temperature‐dependent phase behavior that can be harnessed to produce stimuli‐responsive biomaterials, such as nanoparticles or injectable drug delivery depots. As ELPs are genetically encoded, the properties of ELP‐based biomaterials can be controlled with a precision that is unattainable with synthetic polymers. Unique ELP architectures, such as spherical or rod‐like micelles or injectable coacervates, can be designed by manipulating the ELP amino acid sequence and length. ELPs can be loaded with drugs to create controlled, intelligent drug delivery systems. ELPs are biodegradable, nonimmunogenic, and tolerant of therapeutic additives. These qualities make ELPs exquisitely well‐suited to address current challenges in drug delivery and have spurred the development of ELP‐based therapeutics to treat diseases—such as cancer and diabetes—and to promote wound healing. This review focuses on the use of ELPs in drug delivery systems.

Valency is a fundamental principle to control macromolecular interactions and is used to target specific cell types by multivalent ligand−receptor interactions using self-assembled nanoparticle carriers. At the concentrations encountered in solid tumors upon systemic administration, these nanoparticles are, however, likely to show critical micelle concentration (CMC)-dependent disassembly and thus loss of function. To overcome this limitation, core-crosslinkable micelles of genetically encoded resilin-/elastinlike diblock polypeptides were recombinantly synthesized. The amphiphilic constructs were covalently photo-crosslinked through the genetically encoded unnatural amino acid paraazidophenylalanine in their hydrophobic block and they carried different anticancer ligands on their hydrophilic block: the wild-type tenth human fibronectin type III domain, a GRGDSPAS peptideboth targeting α v β 3 integrinand an engineered variant of the third fibronectin type III domain of tenascin C that is a death receptor 5 agonist. Although uncrosslinked micelles lost most of their targeting ability below their CMC, the crosslinked analogues remained active at concentrations up to 1000-fold lower than the CMC, with binding affinities that are comparable to antibodies.

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