Metal nanoclusters (NCs) are emerging as a new class of functional nanomaterials in the area of biological sensing, labelling, imaging and therapy due to their unique physical and chemical properties, such as ultrasmall size, HOMO–LUMO transition, strong luminescence together with good photostability and biocompatibility. A recent surge of interest in this field is the surface functionalization of these metal NCs through which one can tailor their physicochemical properties, such as stability in solution, and strong luminescence, as well as their biodistribution and toxicity in biological systems, which in turn can empower these functionalized NCs with desirable targeting, imaging, and therapeutic ability for biomedical applications. In this review, we first introduce the functionalization strategies for the metal NCs developed in the past few years, followed by highlighting some biomedical applications of these functionalized metal NCs. We then discuss the difference of in vitro and in vivo fate as well as toxicity between various functionalized metal NCs. Finally, we present a short discussion on the current challenges and provide an outlook of the future developments of these functional metal NCs.

Ultrasmall metal nanoclusters (NCs) have attracted increasing attention due to their fascinating physicochemical properties. Today, functional metal NCs are finding growing acceptance in biomedical applications. To achieve a better performance in biomedical applications, metal NCs can be interfaced with biomolecules, such as proteins, peptides, and DNA, to form a new class of biomolecule-NC composites (or bio-NCs in short), which typically show synergistic or novel physicochemical and physiological properties. This feature article focuses on the recent studies emerging at the interface of metal NCs and biomolecules, where the interactions could impart unique physicochemical properties to the metal NCs, as well as mutually regulate biological functions of the bio-NCs. In this article, we first provide a broad overview of key concepts and developments in the novel biomolecule-directed synthesis of metal NCs. A special focus is placed on the key roles of biomolecules in metal NC synthesis. In the second part, we describe how the encapsulated metal NCs affect the structure and function of biomolecules. Followed by that, we discuss several unique synergistic effects observed in the bio-NCs, and illustrate them with examples highlighting their potential biomedical applications. Continued interdisciplinary efforts are required to build up in-depth knowledge about the interfacial chemistry and biology of bio-NCs, which could further pave their ways toward biomedical applications.