**1. Introduction**

One definition of nanotechnology comes from the statement by the US National Science and Technology Council [1], which states: "The essence of nanotechnology is the ability to work at the molecular level, atom by atom, to create large structures with fundamentally new molecular organization. The aim is to exploit these properties by gaining control of structures and devices at atomic, molecular, and supramolecular levels and to learn to efficiently manufacture and use these devices." Other authors describe nanotechnology as the combinatorial study and integration of scientific technological advances and medical engineering at the nanoscale level [2,3]. All these definitions cover the design and manipulation of nanomaterials. Therefore, nanomaterials, which are one dimension smaller than 100 nanometers, enhance physical, chemical, and biological properties of the original material [4].

Over the last few years, nanotechnology and related disciplines have undergone an exponential growth in applications such as nanomedicine, energy and electronics, and the environment and materials because of the unique properties of nanomaterials [5]. Nanomedicine involves the development of nanoparticles (NPs), among other nanocomponents and devices. For the molecular diagnostics, nanomedicine includes treatment and prevention of human diseases thanks to their compatibility with biomolecules [6].

Currently, NPs have an impact and show an increasing presence in many scientific designs and developments [7]. These have a number of disadvantages, such as the cytotoxic e ffects in living organisms, which may limit their use within the clinical setting [8]. However, important advantages, which make them an ideal approach for biomedical applications, such as their intrinsic ability to enter the human body through inhalation, the skin and digestive routes depending on their physicochemical properties potentially accesses vital organs through the blood flow [9]. However, some key factors must be taken into consideration during the bio-nano-interface construction: (i) The interaction of nanoparticles with their ecosystem, mainly with other nanomaterials and biomolecules. Some studies show the possibility of using AgNPs as antibacterial agents thanks to high toxicity against human pathogenic bacteria. In this sense, Singh T. et al. have demonstrated the use of endophytic fungi Alternaria sp. to synthetize AgNPs [10]. (ii) Their physicochemical properties achieve a suitable design such as particle size, shape, dispersity, surface charge, and protein corona e ffects. Protein corona is a complex plasma proteins layer around the NPs that takes place after systemic administration, when nanoparticles are exposed to physiological proximal fluids, which is mostly blood.

The adsorption of dozens of proteins with varying identities and quantities on the NPs can modify their physicochemical identity, cellular uptake, targeting, circulation lifetime in the blood, and influence the physiological response and toxicity [11]. In this sense, a number of molecules can be used to maintain the integrity and stability of NPs in biological fluids [12]. Dutta P.H. et al. synthesized and characterized two types of NPs, AgNPs, and AuNPs, in order to design an antimalarial nanomaterial. For it, they optimized the size, shape, and surface morphology of the bio-synthesized NPs and showed that AgNPs had insignificant and lower cytotoxicity against several human cancer cell lines than AuNPs. [13]. (iii) As well as the interacting bio-compounds (biomolecules, cells, proximal fluids) that favor a physical, chemical, and mechanical relevant process [1,5]. Mirkin showed that siRNA-based gold nanoparticles inhibit its enzymatic degradation and facilitates its uptake by Hela cells [14].

Despite their potential advantages and promising applications, NP entrance in a physiological environment may be problematic due to di fferent intrinsic NP characteristics. These particles may appear embedded in human proximal fluids, inside cells and culture media among others. Thus, there are multiple conditions and a huge variety of biomolecules potentially interacting with the NPs. This previous knowledge is important for predicting their impact [15]. Because of these inherent interactions, the NPs might have a heterogeneous morphology, which is also correlated with the resulting immuno-biocompatibility and safety of these nanomaterials.

In this case, this mini-review focused on the global interactions of NPs and biomolecules in biological environments, which play a critical role in biomedicine applications.
