Proteinous drugs are highly promising therapeutics to treat various diseases. However, they suffer from limited circulation times and severe off-target side effects. Inspired by active membraneless organelles capable of dynamic recruitment and releasing of specific proteins, here, we present the design of coacervates as therapeutic protocells, made from small metabolites (anionic molecules) and simple arginine-rich peptides (cationic motif) through liquid-liquid phase separation. These complex coacervates demonstrate that their assembly and disassembly can be regulated by redox chemistry, which helps to control the release of the therapeutic protein. A model proteinous drugs, tissue plasminogen activator (tPA), can rapidly compartmentalize inside the complex coacervates, and the coacervates formed from peptides conjugated with arginine-glycine-aspartic acid (RGD) motif (a fibrinogen-derived peptide sequence), show selective binding to the thrombus site and thus enhance on-target efficacy of tPA. Furthermore, the burst release of tPA can be controlled by the redox-induced dissolution of the coacervates. Our proof-of-principle complex coacervate system provides insights into the sequestration and release of proteinous drugs from advanced drug delivery systems and represents a step toward the construction of synthetic therapeutic protocells for biomedical applications.

Biomolecules with metals can form supramolecular nanomaterials through coordination assembly, opening new avenues for cancer theranostics and bringing unique insights into personalized nanomedicine. These biomaterials have been considered versatile and innovative nanoagents due to their structure‒function control, biological nature, and simple preparation methods. This review article summarized the recent developments in multicomponent nanomaterials formed from metal coordination interactions with amino acids, peptides, and proteins, together with anticancer drugs, for cancer theranostics. We discussed the role of functional groups anchored in building blocks for coordination interactions, and subsequently, the types of interactions were examined from a structure‒function perspective. Amino acids with different metals and anticancer drugs forming supramolecular nanomaterials and their anticancer mechanisms were highlighted. Peptides with different metals and anticancer drugs, proteins with metals and anticancer drugs used for material formations, and anticancer activity have been discussed. Ultimately, the conclusion and future outlook for multicomponent supramolecular nanomaterials offer fundamental insights into fabrication design and precision medicine.