biosensors Review Biomedical Applications of Liquid Metal Nanoparticles: A Critical Review Haiyue Li 1, Ruirui Qiao 2, Thomas P. Davis 2,* and Shi-Yang Tang 3,* 1 Department of Chemistry and Biochemistry, University of California, San Diego, CA 92093, USA; [email protected] 2 ARC Centre of Excellence in Convergent Bio-Nano Science and Technology and Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD 4072, Australia; [email protected] 3 Department of Electronic, Electrical and Systems Engineering, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK * Correspondence: [email protected] (T.P.D.); [email protected] (S.-Y.T.) Received: 15 October 2020; Accepted: 27 November 2020; Published: 30 November 2020 Abstract: This review is focused on the basic properties, production, functionalization, cytotoxicity, and biomedical applications of liquid metal nanoparticles (LMNPs), with a focus on particles of the size ranging from tens to hundreds of nanometers. Applications, including cancer therapy, medical imaging, and pathogen treatment are discussed. LMNPs share similar properties to other metals, such as photothermal conversion ability and a propensity to form surface oxides. Compared to many other metals, especially mercury, the cytotoxicity of gallium is low and is considered by many reports to be safe when applied in vivo. Recent advances in exploring different grafting molecules are reported herein, as surface functionalization is essential to enhance photothermal therapeutic effects of LMNPs or to facilitate drug delivery. This review also outlines properties of LMNPs that can be exploited in making medical imaging contrast agents, ion channel regulators, and anti-pathogenic agents. Finally, a foresight is offered, exemplifying underexplored knowledge and highlighting the research challenges faced by LMNP science and technology in expanding into applications potentially yielding clinical advances. Keywords: liquid metal; nanoparticles; biomedical applications; EGaIn; Galinstan; gallium 1. Introduction Gallium (Ga)-based liquid metal alloys, as metallic fluids at ambient temperature, exhibit fluidic flexibility in shape and size in addition to standard metallic properties, including high thermal and electrical conductivities, high densities, and the ability to respond to electric and magnetic fields [1]. When compared to mercury, the low cytotoxicity of Ga opens up new opportunities for liquid metal materials particularly in bio-related fields [2]. Most metallic elements (all alkali and alkaline earth, and most basic and transition metals) can dissolve in Ga to form alloys [3]. The two most commonly used Ga-based alloys are eutectic gallium indium (EGaIn, 75% Ga and 25% In by weight) [4] and eutectic gallium-indium-tin [5] (Galinstan, which has several composition ratios, typically 68% Ga, 22% In and 10% Sn by weight). EGaIn and Galinstan are notable for their low melting points, 15 and 11 ◦C, respectively. Unlike mercury (also liquid at room temperature), Ga-based alloys are more chemically reactive (as they instantly react with oxygen to form an oxide layer), but far less toxic and possess a negligible vapor pressure [1]. As commercial products, they are accessible to most labs, facilitating widespread research and application. As bulk Ga-based alloys are processed into nanoparticles (NPs), they acquire many unique but useful properties that are beneficial in biomedical applications, as listed below: Biosensors 2020, 10, 196; doi:10.3390/bios10120196 www.mdpi.com/journal/biosensors Biosensors 2020, 10, x FOR PEER REVIEW 2 of 21 As bulk Ga-based alloys are processed into nanoparticles (NPs), they acquire many unique but Biosensorsuseful properties2020, 10, 196 that are beneficial in biomedical applications, as listed below: 2 of 21 (1) Surface oxide layer: One unique property of Ga-based alloys is the existence of a thin layer of (1) oxideSurface that oxide effectively layer: Oneyields unique a core-shell property structure of Ga-based in NPs, alloys under is normal the existence processing of a thinconditions layer of [6].oxide The that oxide effectively skin forms yields rapidly a core-shell when structurethe inner inGa NPs, core under is exposed normal to processingoxygen. The conditions formation [6 ]. ofThe an oxide oxide skin layer forms is beneficial rapidly whenin the theproduction inner Ga of core LMNPs is exposed as it helps to oxygen. stabilize The the formation surface to of an provideoxide layer a barrier is beneficial to particle–particle in the production interactions; of LMNPs this asbecomes it helps particularly stabilize the important surface to when provide smalla barrier NPs to are particle–particle required. interactions; this becomes particularly important when small NPs (2) Aare grafting required. platform: The oxide layer yields a shell that can be exploited to attach or anchor (2) sufaceA grafting functionality—this platform: The oxide is vital layer for yields biomedical a shell applications that can be exploited where stealth to attach and or targeting anchor surface are functionality—this is vital for biomedical applications where stealth and targeting are widely widely required for effective application. required for effective application. (3) Photothermal conversion ability: LMNPs of Ga alloys possess a relatively good photothermal (3) Photothermal conversion ability: LMNPs of Ga alloys possess a relatively good photothermal conversion efficiency (52%) and a wide range of light absorbance (near-infrared light (NIR), conversion efficiency (52%) and a wide range of light absorbance (near-infrared light (NIR), 650–1500 nm) [7], both key features for applications in photothermal therapy. 650–1500 nm) [7], both key features for applications in photothermal therapy. (4) Response to remote signals: LMNPs undergo chemical (leading to morphological) changes (4) Response to remote signals: LMNPs undergo chemical (leading to morphological) changes upon upon the application of an electromagnetic, acoustic, or alternating electric field, potentially the application of an electromagnetic, acoustic, or alternating electric field, potentially providing providinga trigger for a trigger the release for the of loadedrelease drugsof loaded [7–14 drugs]. [7–14]. (5)(5) CancerCancer suppressor: Ga has beenbeen usedused forfor di differentfferent clinical clinical applications applications in in forms forms of of compound compound and andion dueion due to its to ability its ability to modify to modify structures structures of DNA, of DNA, inhibit inhibit activities activities of enzymes, of enzymes, modulate modulate protein proteinsynthesis, synthesis, and alter and the alter permeability the permeabi of plasmality of plasma membrane. membrane. For example, For example, Ga3+ ions Ga have3+ ions shown have showntheragnostic theragnostic effects foreffects hypercalcemia, for hypercalcemia, and therapeutic and therapeutic effects against effects non-Hodgkin’sagainst non-Hodgkin’s lymphoma lymphomaand bladder and cancer bladder [15,16 cancer]. [15,16]. This reviewreview seeks seeks to highlightto highlight exciting exciting advances advances in the in use the of theuse Ga-based of the Ga-based LMNPs for LMNPs biomedical for applications,biomedical applications, including cancer including therapy, cancer medical therapy, imaging, medical and imaging, pathogen and treatment pathogen (Figure treatment1). The (Figure paper will1). 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Thisreviewed review elsewhere is therefore [17–23]. focused This on describingreview is therefore the strategies focused for theon productiondescribing the and strate biofunctionalizationgies for the production of LNMPs and and biofunctionalization the presentation of howof LNMPs these NPsand canthe bepresention used in various of how biomedical these NPs applications. can be used Finally, in various the review biomedical offers aapplications. perspective onFinally, the opportunities the review andoffers challenges a perpective for LMNPs on the in opportunities future biomedical and applicationschallenges for as research LMNPs progresses in future towardsbiomedical clinical applications outcomes. as research progresses towards clinical outcomes. Figure 1. Biomedical applications enabled by Ga-based liquid metal nanoparticles (LMNPs). Biosensors 2020, 10, 196 3 of 21 2. Production of LMNPs The manufacturing process of LMNPs—sonication, the most prevalent top-down synthesis method, generally takes from several minutes to hours—is less time consuming and simpler when compared to the equivalent processes required for synthesizing rigid NPs. While the production and assembly of grafting molecules onto other solid metal particles requires time consuming and complex techniques, co-sonicating bulk liquid metal within a solution containing grafting molecules enables