The History of Nanoscience and Nanotechnology: From Chemical–Physical Applications to Nanomedicine

Abstract

Nanoscience breakthroughs in almost every field of science and nanotechnologies make life easier in this era. Nanoscience and nanotechnology represent an expanding research area, which involves structures, devices, and systems with novel properties and functions due to the arrangement of their atoms on the 1–100 nm scale. The field was subject to a growing public awareness and controversy in the early 2000s, and in turn, the beginnings of commercial applications of nanotechnology. Nanotechnologies contribute to almost every field of science, including physics, materials science, chemistry, biology, computer science, and engineering. Notably, in recent years nanotechnologies have been applied to human health with promising results, especially in the field of cancer treatment. To understand the nature of nanotechnology, it is helpful to review the timeline of discoveries that brought us to the current understanding of this science. This review illustrates the progress and main principles of nanoscience and nanotechnology and represents the pre-modern as well as modern timeline era of discoveries and milestones in these fields.

Full text

molecules
Review
The History of Nanoscience and Nanotechnology:
From Chemical–Physical Applications
to Nanomedicine
Samer Bayda 1, * , Muhammad Adeel 2,3, Tiziano Tuccinardi 4, Marco Cordani 5and
Flavio Rizzolio 2, 6, *
1Department of Chemistry, Faculty of Sciences, Jinan University, Tripoli 818, Lebanon
2Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy;
muhammad.adeel@unive.it
3PhD School in Science and Technology of Bio and Nanomaterials, University Ca’ Foscari of Venice,
30170 Venice, Italy
4Department of Pharmacy, University of Pisa, 56126 Pisa, Italy; tiziano.tuccinardi@farm.unipi.it
5Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA Nanociencia), 28049 Madrid, Spain;
marco.cordani@imdea.org
6Department of Molecular science and Nanosystems, University Ca’ Foscari of Venice, 30170 Venice, Italy
*Correspondence: samer.bayda@jinan.edu.lb (S.B.); flavio.rizzolio@unive.it (F.R.); Tel.: +961-06-447
907 (S.B.); +39-0434-659026 (F.R.)
Academic Editor: Alejandro Baeza
Received: 7 November 2019; Accepted: 20 December 2019; Published: 27 December 2019


Abstract:
Nanoscience breakthroughs in almost every field of science and nanotechnologies make
life easier in this era. Nanoscience and nanotechnology represent an expanding research area,
which involves structures, devices, and systems with novel properties and functions due to the
arrangement of their atoms on the 1–100 nm scale. The field was subject to a growing public
awareness and controversy in the early 2000s, and in turn, the beginnings of commercial applications
of nanotechnology. Nanotechnologies contribute to almost every field of science, including physics,
materials science, chemistry, biology, computer science, and engineering. Notably, in recent years
nanotechnologies have been applied to human health with promising results, especially in the field of
cancer treatment. To understand the nature of nanotechnology, it is helpful to review the timeline of
discoveries that brought us to the current understanding of this science. This review illustrates the
progress and main principles of nanoscience and nanotechnology and represents the pre-modern as
well as modern timeline era of discoveries and milestones in these fields.
Keywords: nanoscience; nanotechnology; nanomaterials; nanoparticles; nanomedicine
1. Definition of Nanoscience and Nanotechnology
The prefix ‘nano’ is referred to a Greek prefix meaning ‘dwarf’ or something very small and
depicts one thousand millionth of a meter (10
−9
m). We should distinguish between nanoscience,
and nanotechnology. Nanoscience is the study of structures and molecules on the scales of nanometers
ranging between 1 and 100 nm, and the technology that utilizes it in practical applications such as
devices etc. is called nanotechnology [
1
]. As a comparison, one must realize that a single human hair
is 60,000 nm thickness and the DNA double helix has a radius of 1 nm (Figure 1) [
2
]. The development
of nanoscience can be traced to the time of the Greeks and Democritus in the 5th century B.C.,
when scientists considered the question of whether matter is continuous, and thus infinitely divisible
into smaller pieces, or composed of small, indivisible and indestructible particles, which scientists now
call atoms.
Molecules 2020,25, 112; doi:10.3390/molecules25010112 www.mdpi.com/journal/molecules

Molecules 2020,25, 112 2 of 15
Molecules 2019, 24, x FOR PEER REVIEW 2 of 14
smaller pieces, or composed of small, indivisible and indestructible particles, which scientists now
call atoms.
Nanotechnology is one of the most promising technologies of the 21st century. It is the ability to
convert the nanoscience theory to useful applications by observing, measuring, manipulating,
assembling, controlling and manufacturing matter at the nanometer scale. The National
Nanotechnology Initiative (NNI) in the United States define Nanotechnology as “a science,
engineering, and technology conducted at the nanoscale (1 to 100 nm), where unique phenomena
enable novel applications in a wide range of fields, from chemistry, physics and biology, to medicine,
engineering and electronics” [3]. This definition suggests the presence of two conditions for
nanotechnology. The first is an issue of scale: nanotechnology is concerned to use structures by
controlling their shape and size at nanometer scale. The second issue has to do with novelty:
nanotechnology must deal with small things in a way that takes advantage of some properties
because of the nanoscale [4].
We should distinguish between nanoscience and nanotechnology. Nanoscience is a convergence
of physics, materials science and biology, which deal with manipulation of materials at atomic and
molecular scales; while nanotechnology is the ability to observe measure, manipulate, assemble,
control, and manufacture matter at the nanometer scale. There are some reports available, which
provided the history of nanoscience and technology, but no report is available which summarize the
nanoscience and technology from the beginning to that era with progressive events. Therefore, it is
of the utmost requirements to summarize main events in nanoscience and technology to completely
understand their development in this field.
Figure 1. A comparison of sizes of nanomaterial. Reproduced with permission from reference [2].
2. The Imaginative Pioneers of Nanotechnology
The American physicist and Nobel Prize laureate Richard Feynman introduce the concept of
nanotechnology in 1959. During the annual meeting of the American Physical Society, Feynman
presented a lecture entitled “There’s Plenty of Room at the Bottom” at the California Institute of
Technology (Caltech). In this lecture, Feynman made the hypothesis “Why can’t we write the entire
24 volumes of the Encyclopedia Britannica on the head of a pin?”, and described a vision of using
machines to construct smaller machines and down to the molecular level [5]. This new idea
demonstrated that Feynman’s hypotheses have been proven correct, and for these reasons, he is
considered the father of modern nanotechnology. After fifteen years, Norio Taniguchi, a Japanese
scientist was the first to use and define the term “nanotechnology” in 1974 as: “nanotechnology
mainly consists of the processing of separation, consolidation, and deformation of materials by one
atom or one molecule” [6].
Figure 1. A comparison of sizes of nanomaterial. Reproduced with permission from reference [2].
Nanotechnology is one of the most promising technologies of the 21st century. It is
the ability to convert the nanoscience theory to useful applications by observing, measuring,
manipulating, assembling, controlling and manufacturing matter at the nanometer scale. The National
Nanotechnology Initiative (NNI) in the United States define Nanotechnology as “a science, engineering,
and technology conducted at the nanoscale (1 to 100 nm), where unique phenomena enable novel
applications in a wide range of fields, from chemistry, physics and biology, to medicine, engineering
and electronics” [
3
]. This definition suggests the presence of two conditions for nanotechnology.
The first is an issue of scale: nanotechnology is concerned to use structures by controlling their shape
and size at nanometer scale. The second issue has to do with novelty: nanotechnology must deal with
small things in a way that takes advantage of some properties because of the nanoscale [4].
We should distinguish between nanoscience and nanotechnology. Nanoscience is a convergence
of physics, materials science and biology, which deal with manipulation of materials at atomic and
molecular scales; while nanotechnology is the ability to observe measure, manipulate, assemble,
control, and manufacture matter at the nanometer scale. There are some reports available, which
provided the history of nanoscience and technology, but no report is available which summarize the
nanoscience and technology from the beginning to that era with progressive events. Therefore, it is
of the utmost requirements to summarize main events in nanoscience and technology to completely
understand their development in this field.
2. The Imaginative Pioneers of Nanotechnology
The American physicist and Nobel Prize laureate Richard Feynman introduce the concept of
nanotechnology in 1959. During the annual meeting of the American Physical Society, Feynman
presented a lecture entitled “There’s Plenty of Room at the Bottom” at the California Institute of
Technology (Caltech). In this lecture, Feynman made the hypothesis “Why can’t we write the entire 24
volumes of the Encyclopedia Britannica on the head of a pin?”, and described a vision of using machines
to construct smaller machines and down to the molecular level [
5
]. This new idea demonstrated that
Feynman’s hypotheses have been proven correct, and for these reasons, he is considered the father of
modern nanotechnology. After fifteen years, Norio Taniguchi, a Japanese scientist was the first to use
and define the term “nanotechnology” in 1974 as: “nanotechnology mainly consists of the processing
of separation, consolidation, and deformation of materials by one atom or one molecule” [6].
After Feynman had discovered this new field of research catching the interest of many scientists,
two approaches have been developed describing the different possibilities for the synthesis of
nanostructures. These manufacturing approaches fall under two categories: top-down and bottom-up,
which differ in degrees of quality, speed and cost.

Molecules 2020,25, 112 3 of 15
The top-down approach is essentially the breaking down of bulk material to get nano-sized
particles. This can be achieved by using advanced techniques such as precision engineering and
lithography which have been developed and optimized by industry during recent decades. Precision
engineering supports the majority of the micro-electronics industry during the entire production
process, and the high performance can be achieved through the use of a combination of improvements.
These include the use of advanced nanostructure based on diamond or cubic boron nitride and sensors
for size control, combined with numerical control and advanced servo-drive technologies. Lithography
involves the patterning of a surface through exposure to light, ions or electrons, and the deposition of
material on to that surface to produce the desired material [7].
The bottom-up approach refers to the build-up of nanostructures from the bottom: atom-by-atom
or molecule-by-molecule by physical and chemical methods which are in a nanoscale range (1 nm to
100 nm) using controlled manipulation of self-assembly of atoms and molecules. Chemical synthesis
is a method of producing rough materials which can be used either directly in product in their bulk
disordered form, or as the building blocks of more advanced ordered materials. Self-assembly is a
bottom-up approach in which atoms or molecules organize themselves into ordered nanostructures
by chemical-physical interactions between them. Positional assembly is the only technique in which
single atoms, molecules or cluster can be positioned freely one-by-one [7].
The general concept of top down and bottom up and different methods adopted to synthesized
nanoparticles by using these techniques are summarized in Figure 2. In 1986, K. Eric Drexler published
the first book on nanotechnology “Engines of Creation: The Coming Era of Nanotechnology”, which
led to the theory of “molecular engineering” becoming more popular [
8
]. Drexler described the
build-up of complex machines from individual atoms, which can independently manipulate molecules
and atoms and thereby produces self-assembly nanotructures. Later on, in 1991, Drexler, Peterson and
Pergamit published another book entitled “Unbounding the Future: the Nanotechnology Revolution”
in which they use the terms “nanobots” or “assemblers” for nano processes in medicine applications
and then the famous term “nanomedicine” was used for the first time after that [9].
Molecules 2019, 24, x FOR PEER REVIEW 3 of 14
After Feynman had discovered this new field of research catching the interest of many scientists,
two approaches have been developed describing the different possibilities for the synthesis of
nanostructures. These manufacturing approaches fall under two categories: top-down and bottom-
up, which differ in degrees of quality, speed and cost.
The top-down approach is essentially the breaking down of bulk material to get nano-sized
particles. This can be achieved by using advanced techniques such as precision engineering and
lithography which have been developed and optimized by industry during recent decades. Precision
engineering supports the majority of the micro-electronics industry during the entire production
process, and the high performance can be achieved through the use of a combination of
improvements. These include the use of advanced nanostructure based on diamond or cubic boron
nitride and sensors for size control, combined with numerical control and advanced servo-drive
technologies. Lithography involves the patterning of a surface through exposure to light, ions or
electrons, and the deposition of material on to that surface to produce the desired material [7].
The bottom-up approach refers to the build-up of nanostructures from the bottom: atom-by-
atom or molecule-by-molecule by physical and chemical methods which are in a nanoscale range (1
nm to 100 nm) using controlled manipulation of self-assembly of atoms and molecules. Chemical
synthesis is a method of producing rough materials which can be used either directly in product in
their bulk disordered form, or as the building blocks of more advanced ordered materials. Self-
assembly is a bottom-up approach in which atoms or molecules organize themselves into ordered
nanostructures by chemical-physical interactions between them. Positional assembly is the only
technique in which single atoms, molecules or cluster can be positioned freely one-by-one [7].
The general concept of top down and bottom up and different methods adopted to synthesized
nanoparticles by using these techniques are summarized in Figure 2. In 1986, K. Eric Drexler
published the first book on nanotechnology “Engines of Creation: The Coming Era of
Nanotechnology”, which led to the theory of “molecular engineering” becoming more popular [8].
Drexler described the build-up of complex machines from individual atoms, which can
independently manipulate molecules and atoms and thereby produces self-assembly nanotructures.
Later on, in 1991, Drexler, Peterson and Pergamit published another book entitled “Unbounding the
Future: the Nanotechnology Revolution” in which they use the terms “nanobots” or “assemblers” for
nano processes in medicine applications and then the famous term “nanomedicine” was used for the
first time after that [9].
Figure 2. The concept of top down and bottom up technology: different methods for nanoparticle
synthesis.
Bottom UP
TOP Down
Vapour
deposition
Sol gel
Chemical/
Electrochemi
cal
Bio
Reduction
Atomic/
Molecular
Condensation
Atoms &
Molecules
Nanoparticles
Nanoparticles
Bulk Material
Mechanical
Process
Thermal
Process
Optical
Process
Sputtering
Chemical
Etching
Nanoparticle
Synthesis
Figure 2.
The concept of top down and bottom up technology: different methods for
nanoparticle synthesis.
3. History of Nanotechnology
Nanoparticles and structures have been used by humans in fourth century AD, by the Roman,
which demonstrated one of the most interesting examples of nanotechnology in the ancient world.

Molecules 2020,25, 112 4 of 15
The Lycurgus cup, from the British Museum collection, represents one of the most outstanding
achievements in ancient glass industry. It is the oldest famous example of dichroic glass. Dichroic glass
describes two different types of glass, which change color in certain lighting conditions. This means
that the Cup have two different colors: the glass appears green in direct light, and red-purple when
light shines through the glass (Figure 3) [10].
Molecules 2019, 24, x FOR PEER REVIEW 4 of 14
3. History of Nanotechnology
Nanoparticles and structures have been used by humans in fourth century AD, by the Roman,
which demonstrated one of the most interesting examples of nanotechnology in the ancient world.
The Lycurgus cup, from the British Museum collection, represents one of the most outstanding
achievements in ancient glass industry. It is the oldest famous example of dichroic glass. Dichroic
glass describes two different types of glass, which change color in certain lighting conditions. This
means that the Cup have two different colors: the glass appears green in direct light, and red-purple
when light shines through the glass (Figure 3) [10].
Figure 3. The Lycurgus cup. The glass appears green in reflected light (A) and red-purple in
transmitted light (B). Reproduced with permission from reference [10].
In 1990, the scientists analyzed the cup using a transmission electron microscopy (TEM) to
explain the phenomenon of dichroism [11]. The observed dichroism (two colors) is due to the
presence of nanoparticles with 50–100 nm in diameter. X-ray analysis showed that these
nanoparticles are silver-gold (Ag-Au) alloy, with a ratio of Ag:Au of about 7:3, containing in addition
about 10% copper (Cu) dispersed in a glass matrix [12,13]. The Au nanoparticles produce a red color
as result of light absorption (~520 nm). The red-purple color is due to the absorption by the bigger
particles while the green color is attributed to the light scattering by colloidal dispersions of Ag
nanoparticles with a size > 40 nm. The Lycurgus cup is recognized as one of the oldest synthetic
nanomaterials [1]. A similar effect is seen in late medieval church windows, shining a luminous red
and yellow colors due to the fusion of Au and Ag nanoparticles into the glass. Figure 4 shows an
example of the effect of these nanoparticles with different sizes to the stained glass windows [14].
Figure 4. Effect of nanoparticles on the colors of the stained glass windows. Reproduced with
permission from reference [14].
Figure 3.
The Lycurgus cup. The glass appears green in reflected light (
A
) and red-purple in transmitted
light (B). Reproduced with permission from reference [10].
In 1990, the scientists analyzed the cup using a transmission electron microscopy (TEM) to explain
the phenomenon of dichroism [
11
]. The observed dichroism (two colors) is due to the presence
of nanoparticles with 50–100 nm in diameter. X-ray analysis showed that these nanoparticles are
silver-gold (Ag-Au) alloy, with a ratio of Ag:Au of about 7:3, containing in addition about 10% copper
(Cu) dispersed in a glass matrix [
12
,
13
]. The Au nanoparticles produce a red color as result of light
absorption (~520 nm). The red-purple color is due to the absorption by the bigger particles while the
green color is attributed to the light scattering by colloidal dispersions of Ag nanoparticles with a size
>40 nm. The Lycurgus cup is recognized as one of the oldest synthetic nanomaterials [
1
]. A similar
effect is seen in late medieval church windows, shining a luminous red and yellow colors due to the
fusion of Au and Ag nanoparticles into the glass. Figure 4shows an example of the effect of these
nanoparticles with different sizes to the stained glass windows [14].
Molecules 2019, 24, x FOR PEER REVIEW 4 of 14
3. History of Nanotechnology
Nanoparticles and structures have been used by humans in fourth century AD, by the Roman,
which demonstrated one of the most interesting examples of nanotechnology in the ancient world.
The Lycurgus cup, from the British Museum collection, represents one of the most outstanding
achievements in ancient glass industry. It is the oldest famous example of dichroic glass. Dichroic
glass describes two different types of glass, which change color in certain lighting conditions. This
means that the Cup have two different colors: the glass appears green in direct light, and red-purple
when light shines through the glass (Figure 3) [10].
Figure 3. The Lycurgus cup. The glass appears green in reflected light (A) and red-purple in
transmitted light (B). Reproduced with permission from reference [10].
In 1990, the scientists analyzed the cup using a transmission electron microscopy (TEM) to
explain the phenomenon of dichroism [11]. The observed dichroism (two colors) is due to the
presence of nanoparticles with 50–100 nm in diameter. X-ray analysis showed that these
nanoparticles are silver-gold (Ag-Au) alloy, with a ratio of Ag:Au of about 7:3, containing in addition
about 10% copper (Cu) dispersed in a glass matrix [12,13]. The Au nanoparticles produce a red color
as result of light absorption (~520 nm). The red-purple color is due to the absorption by the bigger
particles while the green color is attributed to the light scattering by colloidal dispersions of Ag
nanoparticles with a size > 40 nm. The Lycurgus cup is recognized as one of the oldest synthetic
nanomaterials [1]. A similar effect is seen in late medieval church windows, shining a luminous red
and yellow colors due to the fusion of Au and Ag nanoparticles into the glass. Figure 4 shows an
example of the effect of these nanoparticles with different sizes to the stained glass windows [14].
Figure 4. Effect of nanoparticles on the colors of the stained glass windows. Reproduced with
permission from reference [14].
Figure 4.
Effect of nanoparticles on the colors of the stained glass windows. Reproduced with
permission from reference [14].
During the 9th–17th centuries, glowing, glittering “luster” ceramic glazes used in the Islamic
world, and later in Europe contained Ag or copper (Cu) or other nanoparticles [
15
]. The Italians

Molecules 2020,25, 112 5 of 15
also employed nanoparticles in creating Renaissance pottery during 16th century [
16
]. They were
influenced by Ottoman techniques: during the 13th–18th centuries, to produce “Damascus” saber
blades, cementite nanowires and carbon nanotubes were used to provide strength, resilience, and the
ability to hold a keen edge [
17
]. These colors and material properties were produced intentionally
for hundreds of years. Medieval artists and forgers, however, did not know the cause of these
surprising effects.
In 1857, Michael Faraday studied the preparation and properties of colloidal suspensions of
“Ruby” gold. Their unique optical and electronic properties make them some of the most interesting
nanoparticles. Faraday demonstrated how gold nanoparticles produce different-colored solutions
under certain lighting conditions [
18
]. The progression in nanotechnology due to the blessings of
nanoscience are summarized in the Figure 5.
Molecules 2019, 24, x FOR PEER REVIEW 5 of 14
During the 9th–17th centuries, glowing, glittering “luster” ceramic glazes used in the Islamic
world, and later in Europe contained Ag or copper (Cu) or other nanoparticles [15]. The Italians also
employed nanoparticles in creating Renaissance pottery during 16th century [16]. They were
influenced by Ottoman techniques: during the 13th–18th centuries, to produce “Damascus” saber
blades, cementite nanowires and carbon nanotubes were used to provide strength, resilience, and the
ability to hold a keen edge [17]. These colors and material properties were produced intentionally for
hundreds of years. Medieval artists and forgers, however, did not know the cause of these surprising
effects.
In 1857, Michael Faraday studied the preparation and properties of colloidal suspensions of
“Ruby” gold. Their unique optical and electronic properties make them some of the most interesting
nanoparticles. Faraday demonstrated how gold nanoparticles produce different-colored solutions
under certain lighting conditions [18]. The progression in nanotechnology due to the blessings of
nanoscience are summarized in the Figure 5.
Figure 5. Progresses in Nanotechnology.
4. Modern Era of Nanotechnology
There was a progress in nanotechnology since the early ideas of Feynman until 1981 when the
physicists Gerd Binnig and Heinrich Rohrer invented a new type of microscope at IBM Zurich
Research Laboratory, the Scanning Tunneling Microscope (STM) [19,20]. The STM uses a sharp tip
that moves so close to a conductive surface that the electron wave functions of the atoms in the tip
overlap with the surface atom wave functions. When a voltage is applied, electrons “tunnel” through
the vacuum gap from the atom of the tip into the surface (or vice versa). In 1983, the group published
the first STM image of the Si(111)-7 × 7 reconstructed surface, which nowadays can be routinely
imaged as shown in Figure 6 [21,22].
Figure 5. Progresses in Nanotechnology.
4. Modern Era of Nanotechnology
There was a progress in nanotechnology since the early ideas of Feynman until 1981 when the
physicists Gerd Binnig and Heinrich Rohrer invented a new type of microscope at IBM Zurich Research
Laboratory, the Scanning Tunneling Microscope (STM) [
19
,
20
]. The STM uses a sharp tip that moves so
close to a conductive surface that the electron wave functions of the atoms in the tip overlap with the
surface atom wave functions. When a voltage is applied, electrons “tunnel” through the vacuum gap
from the atom of the tip into the surface (or vice versa). In 1983, the group published the first STM
image of the Si(111)-7
×
7 reconstructed surface, which nowadays can be routinely imaged as shown in
Figure 6[21,22].

Molecules 2020,25, 112 6 of 15
Molecules 2019, 24, x FOR PEER REVIEW 6 of 14
Figure 6. STM image of the Si(111)-7 × 7 reconstructed surface showing atomic scale resolution of the
top-most layer of silicon atoms. Reproduced with permission from reference [22].
A few years later, in 1990, Don Eigler of IBM in Almaden and his colleagues used a STM to
manipulate 35 individual xenon atoms on a nickel surface and formed the letters of IBM logo (Figure
7) [23]. The STM was invented to image surfaces at the atomic scale and has been used as a tool with
which atoms and molecules can be manipulated to create structures. The tunneling current can be
used to selectively break or induce chemical bonds.
Figure 7. 35 Xenon atoms positioned on a nickel (110) substrate using a STM to form IBM logo.
Reproduced with permission from reference [23].
In 1986, Binnig and Rohrer received the Nobel Prize in Physics “for their design of the STM”.
This invention led to the development of the atomic force microscope (AFM) and scanning probe
microscopes (SPM), which are the instruments of choice for nanotechnology researchers today
[24,25]. At the same time, in 1985, Robert Curl, Harold Kroto, and Richard Smalley discovered that
carbon can also exist in the form of very stable spheres, the fullerenes or buckyballs [26]. The carbon
balls with chemical formula C60 or C70 are formed when graphite is evaporated in an inert
atmosphere. A new carbon chemistry has been now developed, and it is possible to enclose metal
atoms and create new organic compounds. A few years later, in 1991, Iijima et al. observed of hollow
graphitic tubes or carbon nanotubes by Transmission Electron Microscopy (TEM) which form
another member of the fullerene family (Figure 8) [27]. The strength and flexibility of carbon
nanotubes make them potentially useful in many nanotechnological applications. Currently, Carbon
nanotubes are used as composite fibers in polymers and beton to improve the mechanical, thermal
and electrical properties of the bulk product. They also have potential applications as field emitters,
energy storage materials, catalysis, and molecular electronic components.
Figure 8. Schematic of a C60 buckyball (Fullerene) (A) and carbon nanotube (B).
Figure 6.
STM image of the Si(111)-7
×
7 reconstructed surface showing atomic scale resolution of the
top-most layer of silicon atoms. Reproduced with permission from reference [22].
A few years later, in 1990, Don Eigler of IBM in Almaden and his colleagues used a STM
to manipulate 35 individual xenon atoms on a nickel surface and formed the letters of IBM logo
(Figure 7) [
23
]. The STM was invented to image surfaces at the atomic scale and has been used as a
tool with which atoms and molecules can be manipulated to create structures. The tunneling current
can be used to selectively break or induce chemical bonds.
Molecules 2019, 24, x FOR PEER REVIEW 6 of 14
Figure 6. STM image of the Si(111)-7 × 7 reconstructed surface showing atomic scale resolution of the
top-most layer of silicon atoms. Reproduced with permission from reference [22].
A few years later, in 1990, Don Eigler of IBM in Almaden and his colleagues used a STM to
manipulate 35 individual xenon atoms on a nickel surface and formed the letters of IBM logo (Figure
7) [23]. The STM was invented to image surfaces at the atomic scale and has been used as a tool with
which atoms and molecules can be manipulated to create structures. The tunneling current can be
used to selectively break or induce chemical bonds.
Figure 7. 35 Xenon atoms positioned on a nickel (110) substrate using a STM to form IBM logo.
Reproduced with permission from reference [23].
In 1986, Binnig and Rohrer received the Nobel Prize in Physics “for their design of the STM”.
This invention led to the development of the atomic force microscope (AFM) and scanning probe
microscopes (SPM), which are the instruments of choice for nanotechnology researchers today
[24,25]. At the same time, in 1985, Robert Curl, Harold Kroto, and Richard Smalley discovered that
carbon can also exist in the form of very stable spheres, the fullerenes or buckyballs [26]. The carbon
balls with chemical formula C60 or C70 are formed when graphite is evaporated in an inert
atmosphere. A new carbon chemistry has been now developed, and it is possible to enclose metal
atoms and create new organic compounds. A few years later, in 1991, Iijima et al. observed of hollow
graphitic tubes or carbon nanotubes by Transmission Electron Microscopy (TEM) which form
another member of the fullerene family (Figure 8) [27]. The strength and flexibility of carbon
nanotubes make them potentially useful in many nanotechnological applications. Currently, Carbon
nanotubes are used as composite fibers in polymers and beton to improve the mechanical, thermal
and electrical properties of the bulk product. They also have potential applications as field emitters,
energy storage materials, catalysis, and molecular electronic components.
Figure 8. Schematic of a C60 buckyball (Fullerene) (A) and carbon nanotube (B).
Figure 7.
35 Xenon atoms positioned on a nickel (110) substrate using a STM to form IBM logo.
Reproduced with permission from reference [23].
In 1986, Binnig and Rohrer received the Nobel Prize in Physics “for their design of the STM”.
This invention led to the development of the atomic force microscope (AFM) and scanning probe
microscopes (SPM), which are the instruments of choice for nanotechnology researchers today [
24
,
25
].
At the same time, in 1985, Robert Curl, Harold Kroto, and Richard Smalley discovered that carbon
can also exist in the form of very stable spheres, the fullerenes or buckyballs [
26
]. The carbon balls
with chemical formula C60 or C70 are formed when graphite is evaporated in an inert atmosphere.
A new carbon chemistry has been now developed, and it is possible to enclose metal atoms and create
new organic compounds. A few years later, in 1991, Iijima et al. observed of hollow graphitic tubes or
carbon nanotubes by Transmission Electron Microscopy (TEM) which form another member of the
fullerene family (Figure 8) [
27
]. The strength and flexibility of carbon nanotubes make them potentially
useful in many nanotechnological applications. Currently, Carbon nanotubes are used as composite
fibers in polymers and beton to improve the mechanical, thermal and electrical properties of the bulk
product. They also have potential applications as field emitters, energy storage materials, catalysis,
and molecular electronic components.
Molecules 2019, 24, x FOR PEER REVIEW 6 of 14
Figure 6. STM image of the Si(111)-7 × 7 reconstructed surface showing atomic scale resolution of the
top-most layer of silicon atoms. Reproduced with permission from reference [22].
A few years later, in 1990, Don Eigler of IBM in Almaden and his colleagues used a STM to
manipulate 35 individual xenon atoms on a nickel surface and formed the letters of IBM logo (Figure
7) [23]. The STM was invented to image surfaces at the atomic scale and has been used as a tool with
which atoms and molecules can be manipulated to create structures. The tunneling current can be
used to selectively break or induce chemical bonds.
Figure 7. 35 Xenon atoms positioned on a nickel (110) substrate using a STM to form IBM logo.
Reproduced with permission from reference [23].
In 1986, Binnig and Rohrer received the Nobel Prize in Physics “for their design of the STM”.
This invention led to the development of the atomic force microscope (AFM) and scanning probe
microscopes (SPM), which are the instruments of choice for nanotechnology researchers today
[24,25]. At the same time, in 1985, Robert Curl, Harold Kroto, and Richard Smalley discovered that
carbon can also exist in the form of very stable spheres, the fullerenes or buckyballs [26]. The carbon
balls with chemical formula C60 or C70 are formed when graphite is evaporated in an inert
atmosphere. A new carbon chemistry has been now developed, and it is possible to enclose metal
atoms and create new organic compounds. A few years later, in 1991, Iijima et al. observed of hollow
graphitic tubes or carbon nanotubes by Transmission Electron Microscopy (TEM) which form
another member of the fullerene family (Figure 8) [27]. The strength and flexibility of carbon
nanotubes make them potentially useful in many nanotechnological applications. Currently, Carbon
nanotubes are used as composite fibers in polymers and beton to improve the mechanical, thermal
and electrical properties of the bulk product. They also have potential applications as field emitters,
energy storage materials, catalysis, and molecular electronic components.
Figure 8. Schematic of a C60 buckyball (Fullerene) (A) and carbon nanotube (B).
Figure 8. Schematic of a C60 buckyball (Fullerene) (A) and carbon nanotube (B).

Molecules 2020,25, 112 7 of 15
In 2004, a new class of carbon nanomaterials called carbon dots (C-dots) with size below 10 nm
was discovered accidentally by Xu et al. during the purification of single-walled carbon nanotubes [
28
].
C-dots with interesting properties have gradually become a rising star as a new nanocarbon member
due to their benign, abundant and inexpensive nature [
29
]. Possessing such superior properties
as low toxicity and good biocompatibility renders C-dots favorable materials for applications in
bioimaging, biosensor and drug delivery [
30
–
35
]. Based on their excellent optical and electronic
properties, C-dots can also offer exciting opportunities for catalysis, energy conversion, photovoltaic
devices and nanoprobes for sensitive ion detection [
36
–
39
]. After the discovery of “graphene” in 2004,
carbon-based materials became the backbone of almost every field of science and engineering.
In the meantime, nanoscience progressed in other fields of science like in computer science,
bio and engineering. Nanoscience and technology progressed in computer science to decrease the
size of a normal computer from a room size to highly efficient moveable laptops. Electrical engineers
progressed to design the complex electrical circuits down to nanoscale level. Also, many advances are
noticed in smart phone technology and other modern electronic devices for daily uses.
At the beginning of 21st century, there was an increased interest in the nanoscience and
nanotechnology fields. In the United States, Feynman’s concept of manipulation of matter at the atomic
level played an important role in shaping national science priorities. During a speech at Caltech on 21
January 2000, President Bill Clinton advocated for the funding of research in the field of nanotechnology.
Three years later, President George W. Bush signed into law the 21st century Nanotechnology Research
and Development Act. The legislation made nanotechnology research a national priority and created
the National Technology Initiative (NNI).
Recently, a number of studies highlighted the huge potential that nanotechnologies play
in biomedicine for the diagnosis and therapy of many human diseases [
40
]. In this regard,
bio-nanotechnology is considered by many experts as one of the most intriguing field of application of
nanoscience. During recent decades, the applications of nanotechnology in many biology related areas
such as diagnosis, drug delivery, and molecular imaging are being intensively researched and offered
excellent results. Remarkably, a plethora of medical-related products containing nanomaterials are
currently on the market in the USA. Examples of “nanopharmaceuticals” include nanomaterials for drug
delivery and regenerative medicine, as well as nanoparticles with antibacterial activities or functional
nanostructures used for biomarker detection like nanobiochips, nanoelectrodes, or nanobiosensors [
41
].
One of the most important applications of nanotechnology to molecular biology has been related
to nucleic acids. In 2006, Paul Rothemund developed the “scaffolded DNA origami”, by enhancing the
complexity and size of self-assembled DNA nanostructures in a “one-pot” reaction [
42
]. The conceptual
foundation for DNA nanotechnology was first laid out by Nadrian Seeman in 1982: “It is possible to
generate sequences of oligomeric nucleic acids, which will preferentially associate to form migrationally
immobile junctions, rather than linear duplexes, as they usually do” [
43
]. DNA nanotechnology has
already become an interdisciplinary research area, with researchers from physics, chemistry, materials
science, computer science, and medicine coming together to find solutions for future challenges in
nanotechnology [
44
–
47
]. Notably, years of extensive studied made possible to use DNA and other
biopolymers directly in array technologies for sensing and diagnostic applications.
Remarkable progresses have been made also in the field of nano-oncology by improving the
efficacy of traditional chemotherapy drugs for a plethora of aggressive human cancers [48,49]. These
advances have been achieved by targeting the tumour site with several functional molecules including
nanoparticles, antibodies and cytotoxic agents. In this context, many studies showed that nanomaterials
can be employed itself or to deliver therapeutic molecules to modulate essential biological processes,
like autophagy, metabolism or oxidative stress, exerting anticancer activity [50].
Hence, nano-oncology is a very attractive application of nanoscience and allows for the
improvement of tumour response rates in addition to a significant reduction of the systemic toxicity
associated with current chemotherapy treatments.

Molecules 2020,25, 112 8 of 15
Nanotechnology has been used to improve the environment and to produce more efficient and
cost-effective energy, such as generating less pollution during the manufacture of materials, producing
solar cells that generate electricity at a competitive cost, cleaning up organic chemicals polluting
groundwater, and cleaning volatile organic compounds (VOCs) from air.
However, the application of computational approaches to nanomedicine is yet underdeveloped
and is an exigent area of research. The need for computational applications at the nano scale has given
rise to the field of nanoinformatics.
Powerful machine-learning algorithms and predictive analytics can considerably facilitate the
design of more efficient nanocarriers. Such algorithms provide predictive knowledge on future data,
have been mainly applied for predicting cellular uptake, activity, and cytotoxicity of nanoparticles.
Data mining, network analysis, quantitative structure-property relationship (QSPR), quantitative
structure–activity relationship (QSAR), and ADMET (absorption, distribution, metabolism, excretion,
and toxicity) predictors are some of the other prominent property evaluations being carried out
in nanoinformatics.
Nanoinformatics has provided a major supplementary platform for nanoparticle design and
analysis to overcome such
in vitro
barriers. Nanoinformatics exclusively deals with the assembling,
sharing, envisaging, modeling, and evaluation of significant nanoscale level data and information.
Nanoinformatics also facilitates chemotherapy by improving the nano-modeling of the tumor cells and
aids detection of the drug-resistant tumors easily. Hyperthermia-based targeted drug delivery and
gene therapy approaches are the latest nanoinformatics techniques proven to treat cancer with least
side effects [51].
5. Conclusions
The progress of nanoscience and nanotechnology in different fields of science has expanded in
different directions, to observe things from micro to nano, to even smaller scale sizes by different
microscopes in physics, from micro size bulk matter to small size carbon dots in chemistry, from room
size computers to mobile slim size laptops in computer science, and to observe deeply the behavior
of the cell
0
s nucleus to study single complicated biomolecules at the nano level in biological science.
All these progressions in different fields of science have been generally overviewed and summarized
in Figure 9.
In only a few decades, nanotechnology and nanoscience have become of fundamental importance
to industrial applications and medical devices, such as diagnostic biosensors, drug delivery systems,
and imaging probes. For example, in the food industry, nanomaterials have been exploited to increase
drastically the production, packaging, shelf life, and bioavailability of nutrients. In contrast, zinc oxide
nanostructures display antimicrobial activity against food-borne bacteria, and a plethora of different
nanomaterials are nowadays used for diagnostic purposes as food sensors to detect food quality and
safety [52].
Nanomaterials are being used to build a new generation of solar cells, hydrogen fuel cells,
and novel hydrogen storage systems capable of delivering clean energy to countries still reliant on
traditional, non-renewable contaminating fuels.
However, the most significant advances in nanotechnology fall in the broad field of biomedicine
and especially in cancer therapeutics because of their great potential to offer innovative solutions to
overcome the limitations deriving by traditional chemotherapy and radiotherapy approaches.
Recent advances made in the fields of physic, chemistry and material sciences have provided a
number of nanomaterials with unique properties, which are expected to improve the treatment of many
tumors otherwise resistant to current therapies. This will be possible by merit of their intrinsic cytotoxic
activity and/or because of their capability to act as nanocarriers to deliver therapeutic molecules, such
as drugs, proteins, nucleic acids or immune agents. These innovative biomedical applications are
currently exploited in a variety of clinical trials and, in the near future, may support major development
in the therapy of cancer.

Molecules 2020,25, 112 9 of 15
Molecules 2019, 24, x FOR PEER REVIEW 9 of 14
In 2018, the budget for NNI was 1.2 billion dollars ($) to support nanoscience, engineering and
technology. Still, scientists are working for new breakthroughs in nanoscience and nanotechnology
in order to make human life easier and more comfortable.
Figure 9. Progress in nanoscience and nanotechnology in different fields of science.
In this context, Table 1 presents the historical development of nanoscience and nanotechnology.
Table 1. Evolution Timeline of Nanoscience and Nanotechnology.
Year Event References
4th Century Lycurgus Cup (Colored glass). [12]
500–1450 Cathedrals (Stained glasses windows). [53]
1450–1600 Deruta Pottery (Iridescent/metallic clusters). [53]
1857 Michael Faraday (Synthesis of colloidal ruby gold nanoparticles). [18]
1908 Gustav Mie (Light scattering nanoparticles). [54]
1928 Edward Synge (Near-field optical microscope). [55]
1931 Max Knoll and Ernst Ruska (invention of transmission electron microscope (TEM)). [56,57]
1936 Erwin Müller (Invention of field electron microscope). [58]
1947 William Shockley, Walter Brattain and John Bardeen (Discovery of the semiconductor transistor). [59]
1951 Erwin Müller (Invention of field-ion microscope, first to see atoms on the surface). [60,61]
1953 James Watson and Francis Crick (Discovery of DNA). [62]
1956 Arthur Von Hippel (Molecular Engineering). [63]
1958 Leo Esaki (Electron tunneling). [64]
1959 Richard Feynman (There’s Plenty of Room at the Bottom). [5]
1960 Charles Plank and Edward Rosinski (Zeolites and catalysis). [65]
1963 Stephen Papell (Invention of Ferrofluids). [66]
1965 Gordon E. Moore (Moore’s Law). [67]
1970 Eiji Osawa (Predicted the existence of C60 in the form of icosahedron). [68]
1974 Norio Taniguchi (First use of the term “Nanotechnology”). [6]
1974 Mark A. Ratner and Arieh Aviram (Molecular electronics). [69]
1977 Richard P. Van Duyne (Discovery of Surface Enhanced Raman Spectroscopy (SERS)). [70]
1980 Jacop Sagiv (Discovery of Self-Assembly Monolayers (SAMs)). [71]
1981 Gerd Binnig and Heinrich Rohrer (Invention of Scanning Tunneling Microscope (STM)). [72]
1981 Alexey Ekimov (Discovery of nanocrystalline Quantum Dots in a glass matrix). [73]
1981 Eric Drexler (Molecular Engineering). [74]
1982 Nadrian Seeman (Development of the concept of DNA Nanotechnology). [43,75]
1983 Louis Brus (Discovery of colloidal Quantum Dots). [76,77]
Figure 9. Progress in nanoscience and nanotechnology in different fields of science.
In 2018, the budget for NNI was 1.2 billion dollars ($) to support nanoscience, engineering and
technology. Still, scientists are working for new breakthroughs in nanoscience and nanotechnology in
order to make human life easier and more comfortable.
In this context, Table 1presents the historical development of nanoscience and nanotechnology.
Table 1. Evolution Timeline of Nanoscience and Nanotechnology.
Year Event References
4th Century Lycurgus Cup (Colored glass). [12]
500–1450 Cathedrals (Stained glasses windows). [53]
1450–1600 Deruta Pottery (Iridescent/metallic clusters). [53]
1857 Michael Faraday (Synthesis of colloidal ruby gold nanoparticles). [18]
1908 Gustav Mie (Light scattering nanoparticles). [54]
1928 Edward Synge (Near-field optical microscope). [55]
1931 Max Knoll and Ernst Ruska (invention of transmission electron
microscope (TEM)). [56,57]
1936 Erwin Müller (Invention of field electron microscope). [58]
1947 William Shockley, Walter Brattain and John Bardeen (Discovery of the
semiconductor transistor). [59]
1951 Erwin Müller (Invention of field-ion microscope, first to see atoms on
the surface). [60,61]
1953 James Watson and Francis Crick (Discovery of DNA). [62]
1956 Arthur Von Hippel (Molecular Engineering). [63]
1958 Leo Esaki (Electron tunneling). [64]
1959 Richard Feynman (There’s Plenty of Room at the Bottom). [5]
1960 Charles Plank and Edward Rosinski (Zeolites and catalysis). [65]
1963 Stephen Papell (Invention of Ferrofluids). [66]
1965 Gordon E. Moore (Moore’s Law). [67]
1970 Eiji Osawa (Predicted the existence of C60 in the form of icosahedron). [68]
1974 Norio Taniguchi (First use of the term “Nanotechnology”). [6]

Molecules 2020,25, 112 10 of 15
Table 1. Cont.
Year Event References
1974 Mark A. Ratner and Arieh Aviram (Molecular electronics). [69]
1977 Richard P. Van Duyne (Discovery of Surface Enhanced Raman
Spectroscopy (SERS)). [70]
1980 Jacop Sagiv (Discovery of Self-Assembly Monolayers (SAMs)). [71]
1981 Gerd Binnig and Heinrich Rohrer (Invention of Scanning Tunneling
Microscope (STM)). [72]
1981 Alexey Ekimov (Discovery of nanocrystalline Quantum Dots in a
glass matrix). [73]
1981 Eric Drexler (Molecular Engineering). [74]
1982 Nadrian Seeman (Development of the concept of DNA
Nanotechnology). [43,75]
1983 Louis Brus (Discovery of colloidal Quantum Dots). [76,77]
1985 Richard Smalley, Robert Curl and Harold Kroto (Discovery of
Buckminsterfullerenes C60). [26]
1986 Gerd Binnig, Christoph Gerber and Calvin F. Quate (Invention of
Atomic Force Microscope (AFM). [24]
1987 Dimitri Averin and Konstantin Likharev (Single-Electron Tunneling
(SET) transistor). [78]
1990 Donald Eigler and Erhard Schweizer (Arranged of individual Xenon
atoms to form the letters IBM). [23]
1991 Sumio Iijima (Discovery of Multi-wall Carbon nanotubes). [27]
1992 Charles T. Kresge (Discovery of mesoporous silica MCM-41). [79,80]
1993 Sumio Iijima and Donald Bethune (Discovery of Single-wall Carbon
nanotubes). [81,82]
1996 Chad Mirkin and Robert Letsinger (SAM of DNA+gold colloids). [83]
1997 Zyvex (First nanotechnology company founded). [84]
1998 Cees Dekker (Creation of a Transistor using carbon nanotubes). [85]
1999 Chad Mirkin (Development of Dip-pen Nanolithography (DPN)). [86]
2000 Mark Hersam and Joseph Lyding (Feedback-Controlled
Lithography (FCL). [87]
2000 President Bill Clinton announces US National Nanotechnology
Initiative (NNI). [88]
2001
Carlo Montemagno (Molecular nanomachines: molecular motor (rotor)
with nanoscale silicon devices). [89]
2002 Cees Dekker (Carbon nanotubes functionalized with DNA). [90]
2003 President George W. Bush signed into law the 21st Century
Nanotechnology Research and Development Act. [91]
2003 Naomi Halas (Development of gold nanoshells). [92,93]
2004 Andre Geim and Konstantin Novoselov (Discovery of graphene). [94]
2004 Xu et al. (Discovery of Fluorescent Carbon dots). [28]
2005 James Tour (Nanocar with turning buckyball wheels). [95,96]
2006 Paul Rothemund (DNA origami). [42]
2007 J. Fraser Stoddart (artificial molecular machines: pH-triggered
muscle-like). [97]
2008
Osamu Shimomura, Martin Chalfie and Roger Y. Tsien (Nobel Prize in
Chemistry for the discovery and development of the green fluorescent
protein, GFP).
[98]
2009
Nadrian Seeman (DNA structures fold into 3D rhombohedral crystals).
[99]
2010 IBM (Development of an ultra-fast lithography to create 3D nanoscale
textured surface). [100]
2011
Leonhard Grill (scanning tunneling microscope (STM) describes the
electronic and mechanical properties of individual molecules and the
polymer chains).
[101]
2016
Jean-Pierre Sauvage, Sir J. Fraser Stoddart and Bernard L. Feringa
(Nobel Prize in Chemistry for the design and synthesis of
molecular machines).
[102]
2017 Nobel Prize in Physics 2017: Gravitational waves. [103]
2018 World’s smallest tic-tac-toe game board made with DNA. [104]
2018 Shrinking objects to the nanoscale. [105]

Molecules 2020,25, 112 11 of 15
Author Contributions:
Conceptualization, S.B. and F.R.; writing—Original draft preparation, S.B.;
writing—Review and editing, S.B., M.A., T.T., and M.C.; supervision, F.R. All authors have read and agreed to the
published version of the manuscript.
Funding: This research was funded by AIRC IG 2019 (No.23566).
Acknowledgments: Authors are thankful to Fondazione AIRC per la Ricerca sul Cancro for funding.
Conflicts of Interest: The authors declare no conflict of interest.
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