Multifunctional biomolecule nanostructures for cancer therapy

Abstract

Biomolecule-based nanostructures are inherently multifunctional and harbour diverse biological activities, which can be explored for cancer nanomedicine. The supramolecular properties of biomolecules can be precisely programmed for the design of smart drug delivery vehicles, enabling efficient transport in vivo, targeted drug delivery and combinatorial therapy within a single design. In this Review, we discuss biomolecule-based nanostructures, including polysaccharides, nucleic acids, peptides and proteins, and highlight their enormous design space for multifunctional nanomedicines. We identify key challenges in cancer nanomedicine that can be addressed by biomolecule-based nanostructures and survey the distinct biological activities, programmability and in vivo behaviour of biomolecule-based nanostructures. Finally, we discuss challenges in the rational design, characterization and fabrication of biomolecule-based nanostructures, and identify obstacles that need to be overcome to enable clinical translation.

Keywords: Cancer therapy; Nanotechnology in cancer.

Fig. 1. Functional elements in antitumour multifunctional nanomedicines.

a–d | Surface ligands recognize tumour-associated molecules and epitopes for tumour targeting, penetration and therapy. Ligands can be attached through chemical conjunction (part a), hydrophobic interaction (part b) or electrostatic adsorption onto the nanoparticle surface (part c), or integrated as a functional motif into a peptide- or nucleic-acid-based molecular design (part d). e–g | Surface coatings shield the internal structure from non-specific nano–bio interactions and prevent early clearance during transport and distribution. e | Low protein adsorption on bioinert materials. f | Anti-phagocytosis molecules. g | Blood-cell-derived membrane camouflage. h–k | Combination therapy or theranostic designs may be coupled with antitumour drugs. h | Multiple drug loading. i | Real-time imaging. j | Magnetic resonance steering. k | Phototherapy. l–o | Stimuli-responsive elements. l | Degradable building blocks trigger the disassembly of the nanocarrier to release its contents. m | Surface functionalities for selective activation by a stimulus. Bioactive components may be released or exposed on the nanostructure surface, which can be further monitored in real time by using quenchable or activable imaging agents. n | Environmental stimuli may induce structural transformation of nanostructures, often through stimuli-triggered re-assembly of the building units. o | Nanosurfaces may reverse their overall charge in specific microenvironmental niches.

Fig. 2. Nucleic-acid-based nanostructures for cancer therapy.

Nucleic-acid-based nanostructures, including DNA, RNA, DNA–RNA and heterologous hybrid nanostructures, can be constructed with high spatial accuracy in different dimensions, using tile assembly, origami techniques, rolling circle amplification (RCA), nanoparticle-templated assembly and in silico design (for example, caDNAno, a software package for DNA origami design; NanoTiler, a computer program for RNA nanostructure design). These nanostructures, such as tetrahedrons, nanohydrogels, spherical structures, nanocapsules, origamis and dynamic machines^,, can be applied as multifunctional anticancer systems. CaDNAno interface reprinted with permission from ref., OUP. NanoTiler program reprinted with permission from ref., Elsevier. Tetrahedron reprinted from ref., Springer Nature Limited. Spherical nucleic acids reprinted with permission from ref., ACS. Nanocapsule reprinted with permission from ref., Wiley. Origami reprinted with permission from ref., ACS. Dynamic machine reprinted with permission from ref., AAAS.

Fig. 3. Development of peptide-based multifunctional nanostructures.

Peptides and peptide-based building blocks are designed or selected according to their physicochemical properties and biological functions. By optimizing these characteristics, the self-assembly and supramolecular behaviour (for example, size, shape, surface functional groups, stimuli responsiveness) and biological activities (for example, targeting, cell penetration, therapeutic effects) can be manipulated to achieve optimal performance. The next-generation peptide-based multifunctional nanomedicines will benefit from computationally assisted design, precisely controlled fabrication (for example, microfluidic platforms) and systematic biological data, as well as advanced screening techniques.