Gold nanoclusters are promising optically functional materials because of their attractive optical properties, such as luminescence, two-photon absorption, photothermal conversion, and photodynamics. Regulating the optical functions of gold nanoclusters and improving their performance have attracted wide interest in biological applications. In this Review, we introduce the principles to manipulate both the intrinsic optical properties and the apparent optical performance of gold nanoclusters. Manipulating the surface ligands and compounding with other nanomaterials are facile and efficient strategies. Based on the regulated optical properties, the gold nanoclusters can be well applied in various biomedical applications from multimodal bioimaging toward theranostics. By correlating structures and optical properties, we expect a better utilization of the optical gold nanoclusters in the biological field.

Gold nanocluster (AuNC) decorated hydrogels have attracted considerable attention as versatile biomaterials. To date AuNCs and hydrogels have mainly been mixed as independent components. Here, we report the use of AuNCs as reactive monomers in the polymerization of hydrogels. We used a free radical polymerization to copolymerize AuNCs with acrylamide and N-acryloyl glycinamide to prepare stimuli-responsive smart hydrogels. Multiple CC bonds were decorated on the surface of the AuNCs as active sites for polymerization. These CC bonds not only protected the structure of the AuNCs from oxidation by free radicals during polymerization but also covalently connected the AuNCs with the polymer chains. This structure ensured good photothermal performance of the AuNCs while preserving the thermoresponsive hydrogen bonds of polymers. Moreover, the copolymerized AuNCs acted as cross-linkers, which improved the mechanical properties of the hydrogels. These smart hydrogels had good stability, efficient photothermal conversion, and a sensitive thermoresponsive. We examined their potential for capture of MDA-MB-231 cells with hyaluronic acid as target molecules. The captured cells were released under 660 nm irradiation. This process of targeted capture and light-controlled remote release could be repeatedly applied. These results suggest that systems based on AuNCs copolymerized with hydrogels have great potential for biomedical applications.

Fluorescent gold nanoclusters with unique luminescence properties have drawn great attention in bioimaging. The gold nanoclusters with controlled multicolor fluorescence may benefit accurate fluorescence imaging. In this work, gold-nanoclusterengineered spiropyran ligands (AuNC-SP) were reported to achieve controlled dual-color imaging under single excitation. Through switching the Forster resonance energy transfer from the gold nanocluster segment to the open-ring state merocyanine by UV−vis irradiation, AuNC-SP possesses reversibly dual-color fluorescence. After AuNC-SP combined with chitosan to form AuNC-SP@CS nanoparticles, the steric protection of chitosan largely improved the oxidative stability of AuNC-SP upon UV irradiation. Moreover, the AuNC-SP@ CS could be internalized within cancer cells and released AuNC-SP that further underwent transportation into the nucleus. Thus, the AuNC-SP@CS exhibits excellent and reversible dual-color fluorescence to label not only the cytoplasm but also the nucleus. We envisage the AuNC-SP@CS as an ideal probe for fine subcellular assays in the cell interior.

Natural extracellular matrix is formed by the assembly of small molecules and macromolecules into a hydrogel-like network that can mechanically support cells and involve in cellular processes. Here, we developed a fluorescent supramolecular hydrogel based on a conjugated oligomer OFBTCO2Na, which facilitated noncovalent assembly through hydrophobic interactions and hydrogen bonds in a molecular scale. The generated dense three-dimensional network endows the supramolecular hydrogel with stretchability and stability. Furthermore, fluorescent OFBTCO2Na in hydrogel acted as a donor, which can excite the acceptor dyes on cells encapsulated in hydrogel via the Förster resonance energy transfer (FRET) mechanism. Investigating the fluorescence signal responsiveness of hydrogel to dynamic mechanical stretching well reflected that enhanced stretching dictated the extent of connection between the cell and matrix, which enables effective FRET at a molecular level and allow spatiotemporally monitoring cell–matrix interactions at the three-dimensional network. Importantly, cells can sense stretch forces by their connection with a hydrogel matrix. The dynamic cell–matrix interaction can be conveniently employed to formulate cell morphology. Therefore, the fluorescent supramolecular hydrogel offers a suitable culture platform not only to investigate cell interactions on interfaces but also to regulate cell behavior at interfaces.

In the view of their ability to be uptaken by cells, colloidal particles can exert diverse physiological effects and are promising vehicles for the intracellular delivery of biologically active substances. Given that the modulation of biomaterial interfaces greatly facilitates the prediction and control of the corresponding cellular responses, the interfacial behavior of hydrophobic dye‐modified gold (Au) nanoclusters (Au NCs) is rationally designed to develop Au NC‐containing emulsions and control their biointerfacial interactions with cell membranes. The observed biological performance is indicative of a physical penetration mechanism. The amphiphilic Au NCs decrease the interfacial energy of two immiscible liquids and hinder droplet coalescence to facilitate the formation of emulsions thermodynamically stabilized by dipole–dipole and hydrophobic interactions. Moreover, the amphiphilic Au NCs are localized on the emulsion droplet surface and form segregated interfacial microdomains that adapt to the membrane structure and facilitate the traverse of the emulsions across the cell membrane via direct penetration. Fast penetration coupled with excellent photophysical performance endows the emulsions with multifluorescence tracing and efficient photothermal killing capabilities. The successful change of the interaction mode between NCs and biological objects and the provision of a universal formulation to modulate biointerfacial interactions are expected to inspire new bioapplications.