Harnessing nanotechnology to expand the toolbox of chemical biology

Abstract

Although nanotechnology often addresses biomedical needs, nanoscale tools can also facilitate broad biological discovery. Nanoscale delivery, imaging, biosensing, and bioreactor technologies may address unmet questions at the interface between chemistry and biology. Currently, many chemical biologists do not include nanomaterials in their toolbox, and few investigators develop nanomaterials in the context of chemical tools to answer biological questions. We reason that the two fields are ripe with opportunity for greater synergy. Nanotechnologies can expand the utility of chemical tools in the hands of chemical biologists, for example, through controlled delivery of reactive and/or toxic compounds or signal-binding events of small molecules in living systems. Conversely, chemical biologists can work with nanotechnologists to address challenging biological questions that are inaccessible to both communities. This Perspective aims to introduce the chemical biology community to nanotechnologies that may expand their methodologies while inspiring nanotechnologists to address questions relevant to chemical biology.

Figure 1.

Major classes of potential contributions of nanotechnology to chemical biology. Potential contributions of nanotechnology to chemical biology is classified into four modules: nanocarriers of bioactive chemicals or delivery (upper-left red quadrant); enzymatic nanoreactors (bottom-left blue quadrant); nanoparticle-based molecular imaging (upper-right yellow quadrant); nanoscale sensors (bottom-right green quadrant).

Figure 2.

Nanoparticle-based delivery of transition metal catalysts for intracellular chemical reactions. a, Transition metal catalysts are immobilized onto the surface of a nanoparticle to facilitate intracellular chemical transformations. b, Encapsulation of Pd(0) catalyst into the nanoparticle core via stepwise synthesis. c, Encapsulation and modulated accessibility of a metal catalyst. The reversible competitive host-guest interactions of cucurbit[7]uril (grey) with tertiary amine moieties surface-coated on nanoparticles (dark blue) or 1-adamantylamine (brown) could modulate the accessibility of transition metal catalyst to inactive substrate (light blue). Intracellular reactions catalyzed by transition-metal-encapsulated nanoparticles including: d, Activation of Rhodamine 110. e, Activation of 5-FU. f, Intracellular Suzuki–Miyaura cross-coupling to generate a mitochondria-localized fluorescent compound. g, Activation of Amsacrine.

Figure 3.

Representative examples of enzymatic nanoreactors. a, A pH-sensitive nanoreactor for interphase hydrolysis of cellulose to glycose catalyzed by cellulase. b, Encapsulation of superoxide dismutase and catalase into Aluminum-based metal-organic frameworks (PCN-333) enhances the active duration and resistance to acidic stress/proteases in the intracellular environment. c, Co-expression of small and large subunits of [Ni-Fe] hydrogenase EcHyd-1 with scaffold protein and coat protein in E. coli leads to the in vivo self-assembly of EcHyd-1 encapsulated in bacteriophage P22 capsids. d, A supramolecular self-assembling nanoreactor for DNA-mediated dynamic recruitment and regulation of β-lactamase in cells. BTA: benzene-1,3,5-tricarboxamide; BLIP: β-lactamase inhibitor protein. e, A DNA-origami based multi-enzyme cascade nanoreactor, which is switchable between two metabolic pathways.

Figure 4.

Nanotechnologies for imaging applications. This application can be classified into four modules: (a) fluorescent dye-loaded/conjugated nanoparticles, (b) intrinsically fluorescent nanoparticles, (c) nanoparticles for several radioiamaging modalities, and (d) dye-bound gold nanoparticle for Raman scattering-based imaging. Scale bar is approximate.

Figure 5.

Examples of optical properties unique to certain nanomaterial imaging agents. a) A large Stokes shift compared to organic fluorophores. b) A narrow full-width half-maximum (FWHM) compared to organic fluorophores. c) Unique photostability as compared to organic fluorophores.

Figure 6.

Examples of nanoscale sensor strategies. Among representative nanoscale sensor strategies are: (a) ‘turn-on sensors’ triggered by fluorescence de-quenching, (b) a silicon nanowire-based electronic sensor, (c) a solvatochromic single-walled carbon nanotube-based sensor, and (d) a FRET (Förster Resonance Energy Transfer) sensor.