Functional Integration of DNA and Peptide-Based Supramolecular Nanoassemblies for Cancer Therapy

Supramolecular assembly is a process in which monomers spontaneously construct highly organized and advanced multimolecular assembly systems and thus has become one of the underlying molecular basis of living system. DNA and peptides, as two of the most critical biomacromolecules, rely on intermolecular recognition-based supramolecular assembly to participate in various life activities. Intracellular delivery of functional nucleic acids and peptides has been widely explored for cancer treatment by reprogramming cell function and fate. However, nucleic acids and peptides suffer from the issues of instability and poor bioavailability. In recent years, DNA and peptides have been widely explored as controllable and functional building blocks for the construction of supramolecular nanoassemblies. DNA and peptide-based nanoassemblies have the capability of protecting DNA and peptide monomers from degradation in plasma and to facilitate their cellular uptake. Moreover, the elaborately designed nucleotide and amino acid sequences can be integrated into building blocks, thus endowing supramolecular nanoassemblies with preset structures and functions for application in specific scenarios. Compared with synthetic polymers, the fascinating properties including sequence programmability, structure designability, function customizability, and predicable stimuli-responsiveness combined endowed DNA and peptide nanoassemblies with programmable supramolecular assembly superiority, which facilitates spatiotemporally controllable assembly and release of drugs.In this Account, we provide a conceptual overview of the latest advances in the supramolecular assembly strategy of DNA and peptides and their biomedical applications, especially in cancer therapy. The principles for DNA and peptide monomer design for application in different scenarios are interpreted, which ensure that the monomers can proceed with effective assembly in a predicted way to form nanoassemblies with appealing properties. This Account is divided into two parts: the polymerization-like assembly of DNA and the supramolecular assembly of peptides. The introduced polymerization-like assembly of DNA mainly includes chain-growth polymerization-like assembly, step-growth polymerization-like assembly, and enzyme-catalyzed covalent polymerization assembly. The supramolecular peptide assembly strategy is classified as hydrophilic-hydrophobic-mediated assembly, multiple-forces-mediated layer-by-layer assembly, and responsive transformation assembly. In each part, we start with the introduction of different assembly strategies and properties, wherein pioneering and representative studies are exemplified. Then, the advantages of nanoassemblies and their potential applications for tumor therapy are subsequently elaborated. The common highlight is the release and action mechanisms of DNA and peptide nanoassemblies in cell function regulation and enhanced cancer therapy efficacy. In the end, we conclude by providing perspectives for the future development of programmable DNA and peptide-based supramolecular assembly in promoting clinical transformation of the current practice in tumor therapy.

Automated summary

Supramolecular assembly is a process that constructs highly organized multimolecular assembly systems, and DNA and peptides have been widely explored as controllable building blocks for the construction of supramolecular nanoassemblies. DNA and peptide-based nanoassemblies possess protective and cellular uptake facilitation capabilities, and their programmable supramolecular assembly superiority enables spatiotemporally controllable assembly and release of drugs.