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Nanoparticle Size Effects in Biomedical Applications

Jayanta Dolai, Kuheli Mandal, and Nikhil R. Jana*

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ABSTRACT: Nanoparticle size plays a central role in determining

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material properties and performance in biomedical applications. A

wide variety of functional nanomaterials and nano-bioconjugates
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have been developed for monitoring biochemical activity, controlling

biological functions, and therapeutic applications. This review
focuses on the role of nanoparticle size (typically in the range of
1−100 nm) in various biomedical applications, the origin of such a
size effect, and the optimum size requirement for the best
performance in different biomedical applications. First, we discuss
various nanoscale units present in life processes along with their size
and functional role. Next, we discuss the size-dependent properties
of some well-known nanoparticles and how those properties are
exploited in different biomedical applications. Next, we discuss the
size-dependent performance of functional nanomaterials and nano-bioconjugates that are used in various biomedical applications.
Then, we highlight some of the best designed nanoparticles of optimum size for specific biomedical applications. Finally, we attempt
to correlate the origin of the evolutionary selection of various nanoscale units in life processes toward specific biological functions.
KEYWORDS: nanoparticle, size effect, biosensor, imaging, in vivo targeting, therapy

1. INTRODUCTION isolation of biomolecules/cells, optical biosensors, detection of

Nanoscience is a rapidly growing branch of interdisciplinary
science that has promising application potential in biomed-
ical,1−4 environmental,5,6 energy,7 and other areas.8 Current
research focuses on size-controlled material synthesis,9−11 the
utilization of size-dependent properties in various applications,
and the design of functional materials with nanoscale units that
cannot be achieved by molecule/bulk materials.12−16 Toward
this direction, a wide variety of nanomaterials is synthesized
with distinct size-dependent properties, and many of them are
commercially available.17,18 Well-known examples are colloidal
quantum dots (QDs) with size-dependent emission proper-
ties,19 colloidal gold/silver nanoparticles with size/shape-
dependent plasmonic properties,20 colloidal iron oxide nano-
particles with size-dependent magnetic properties,2 polymer
micelles, and dendrimers with controllable surface chemis-
try.21−23 These nanomaterials are used as optical detection
probes,19 imaging probes,19 contrast agents,2 photocatalysts,24
solar energy conversion materials,7 electrode materials,25
energy storage materials,26 electronic display materials,25 and
so on.
In biomedical applications, the nanometer-length scale is
unique, as material science meets biology at this length
scale.27,28 Nanoparticles can be used to obtain information on
the biological environment and can be designed for various
biomedical applications, such as fluorescence bioimaging
probes, magnetic resonance imaging (MRI) contrast agents,
biochemical activity, drug delivery carriers, control of
biochemical activity, and prevention/curing of various
diseases.1−4,14,17,27,28 The essential conditions for such
biomedical applications are water dispersibility and termi-
nation with appropriate chemical/biochemical groups. The
reason is that the bioenvironment is essentially an aqueous
phase, and dispersed nanoparticles can access all possible
bioenvironments and interact using surface chemical/bio-
chemical groups. For example, water-insoluble nanodrugs
precipitate near the injection site and are unable to travel
from the injection site to a remote tumor site of the body
through blood circulation. Thus, synthesized inorganic nano-
particles are often transformed to core−shell-type nano-
particles, where the shell is composed of hydrophilic molecules
or polymers.29 More specifically, a library of functional
nanoparticles has been generated through decades of research,
and more recently, these materials have been under intensive
investigation for various biomedical applications.17,29
Received: April 11, 2021
Accepted: June 18, 2021
Published: July 2, 2021

© 2021 American Chemical Society https://doi.org/10.1021/acsanm.1c00987

6471 ACS Appl. Nano Mater. 2021, 4, 6471−6496
ACS Applied Nano Materials
Scheme 1. A Brief Overview of the Theme of the Reviewa
a
It focus on size requirements of functional nanoparticle towards biomedical applications in the context of nanoscale units present in life processes
and to exploit the size-dependent material properties. Finally, the current status of the field and possibilities of advanced biomedical applications are
summarized.
The size of the nanoparticles plays a central role in
biomedical applications. There are three specific reasons for
this size effect. First, the physical and chemical properties of
inorganic nanoparticles are often size-dependent, and to utilize
such properties, an appropriate size is essential.17,19,29 For
example, CdSe-based QDs of 1−6 nm size are required to
utilize their emission properties, and more specifically, blue,
green, yellow, and red emissions require sizes of 2, 3, 4, and 5
nm, respectively. Second, the colloidal property requirement of
nanoparticles restricts their size to less than 100−200 nm, as
larger nanoparticles usually precipitate under a gravitational
attraction.29 Third, biological interactions often require certain
size restrictions that are due to either steric effects during
binding interactions or size restrictions of specific biological
functions or size selection by specific biological compart-
ments.17,19 Although these size effects are reported/empha-
sized in different application contexts,13,14,16,19,20 a generalized
consensus on the role of the particle size has not evolved thus
far.
This review focuses on the optimum size requirement of
nanoparticles for various biomedical applications in the context
of different nanoscale units present in life processes (Scheme
1). In particular, we have focused on the size range of 1−100
nm and the origin of this size effect toward different
biomedical applications. First, we discuss various nanoscale
units that are present in life processes along with their
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functional role. Next, we discuss the size-dependent properties
of some well-known nanoparticles and their biomedical
application potential. Next, we discuss the size effect of
functional nanomaterials in various biomedical applications.
Finally, we highlight some of the best designed nanoparticles
with the optimum size for specific biological functions that are
difficult to achieve by molecular/bulk materials. It has been
concluded that there is a good correlation between various
nanoscale functional units present in life processes and the
optimum size requirement of nanoparticles for various
biomedical applications.
2. ROLE OF VARIOUS NANOSCALE UNITS IN LIFE
PROCESSES
Living organisms exploit a variety of nanoscale units for their
specific biological and biochemical activities. Extensive
research efforts are underway to explore the chemical
composition, the biological function, the role of the size, and
the evolutionary origin of such nanostructures. Examples of
various nanoscale units in life processes are listed in Table 1
and Figure 1.30−60 The most relevant examples are the many
nanoscale units that are present in plant/animal cells, which
are the building blocks of living bodies. A living cell can be
considered to be a unified self-regulating machine that involves
the miniaturization of nanoscale units for the development and
sustainability of complex biochemical networks.44 Cells are
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Table 1. Examples of Some Well-Known Nanoscale Units in Biology along with Their Size and Function
nanoscale units
membrane
lipid raft
endocytic vesicle
microtubule
ion channel
amyloid fibrils
protein microstructures
DNA microstructures
virus
bone microstrucure
tooth microstrucure
kidney stone microstructure
diatom microskeleton
iron oxide in magnetotactic
bacteria
iron oxyhydroxide made by
iron oxidizing bacteria
malarial pigment hemozoin
superhydrophobic biosurface
assembly of photosynthetic
complexes
major components size/shape function refs
lipid, protein two-dimensional surface with separate cell or cell 36
3−8 nm thickness compartment
lipid, cholesterol <50 nm control nonendocytic cell 53,54
uptake
clathrin nanocage, caveolin vesicle 60−120 nm control cellular entry/exit of 31,35
foreign materials
protein 25 nm diameter, up to 100 intracellular transport 57
μm length
protein <1.0 nm diameter control cellular entry/exit of 47,53,58
ions/small molecules
protein, peptide nanowire with 2−5 nm linked to various 48,56
diameter and micron length neurodegenerative disease
globular myoglobin, hollow/core−shell ferritin, nano to micron size signaling, molecular 39,44,55
collagen fibrils, porin nanotube, motor proteins recognition and transport
sugar, organic base, phosphate 0.1−0.2 nm width for minor/ replication 30,50
major groove
Covid 19, Ebola virus, tobacco mosaic virus nano to micron size sphere/ linked to various human 59,60
rod/wire diseases
calcium phosphate 10−100 nm platelet mechanical strength 38,41
calcium phosphate 30 nm width and 60 nm long provide hardness to enamel 43
nanorod
calcium oxalate nano to micron size Kidney disease 40,45
silica nano/micro pores structural feature of small 32,37
green plant
Fe3O4 5−10 nm navigate in sea using Earth’s 42
magnetic field
iron(III) oxyhydroxide 2−3 nm biominerallization of iron 34
iron oxide nano to micron size detoxification of heme unit 49
nano/microporous surface nano to micron size self-cleaning property, high 33,51
adhesive property
chlorophylls, tetrapyrroles, carotenoids nano to micron size sunlight harvesting 46

delineated by a phospholipid/sphingolipid/glycolipid bilayer nm size, which are critical in replication processes.30,50 A

membrane of 3−8 nm thickness along with integrated
transmembrane proteins that separate the cell/cellular
compartment from the outside, maintain elasticity/fluidity,
and control the entry-exit/storage/transfer/exchange of
materials.36,53,54 An advanced understanding of cell membrane
structure reveals the existence of an ordered lateral raft domain
less than 50 nm in size that controls endocytic/nonendocytic
cellular uptake.53 These heterogeneous and dynamic (with
respect to mobility and association−dissociation) nano-
domains are named membrane rafts or lipid rafts. They are
enriched in cholesterol, sphingolipids, saturated lipids, and
lipoproteins that have the potential to form microscopic
domains via protein−lipid or protein−protein clustering. The
entry/exit of foreign materials through the cell membrane that
occurs via molecular recognition and signaling processes is
controlled by the size of the foreign materials.31,35 For
example, essential small molecules such as sugar/amino acid/
ions cross through ion channels or integral plasma protein
pumps via a pore (<1.0 nm diameter) formation, and
macromolecules greater than 10 nm in size cross the
membrane via endocytosis through specific ligand−receptor
interactions.31,53 The endocytotic entry of material is
controlled via a nanoscale clustering of specific proteins, such
as clathrin/caveolin, at the cell surface followed by the
formation of endocytic vesicles 60−120 nm in size.35
A nanoscale assembly of various biomolecules is critical for
their biological functions. The nanoscale assembly of DNA
into a double helix structure is essential for biological function.
DNA consists of major grooves and minor grooves of 0.1−0.2
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nanoscale assembly of various proteins is associated with
different biological functions. Examples include a folded
protein microstructure with nanosize domains of helical
loops present in globular myoglobin, hollow/core−shell
ferritin, collagen fibrils, porin nanotube, and motor pro-
teins.39,44,55 These nanodomain structures are correlated with
membrane signaling and transduction, molecular recognition
and transport, macromolecular activation, regulation, and
processing. Moreover, the modular self-assembly of globular
nanoscale building blocks produces higher-order complex
biological nanostructures. Well-known examples include
anisotropic cytoskeletal tubulin microtubule/actin microfila-
ments of 25 nm in diameter and up to 100 μm in length, where
the intrinsic polarity of the motor head domain of myosin (F-
actin) and dynein (microtubules) are responsible for a
directional clustering.57 These processes are associated with
the transport of cellular cargoes and the displacement of
various intracellular pathogens. A nanoscale aggregation/
assembly of proteins is linked to various neurodegenerative
and other disorders.48,56 In particular, nano/microscale
aggregation of polyglutamine, amyloid protein, α-synuclein,
and insulin is responsible for Huntington’s, Alzheimer’s,
Parkinson’s, and type II diabetes, respectively.14,48,56 The
most common example is the fibrillation of amyloid beta (Aβ)
protein/peptide, which generates micron-length nanowires
that have a 2−5 nm diameter.
Biomineralization is another important aspect that involves
the nucleation of nanoscale units at biological interfaces,
primarily from inorganic precursors, and sometimes nanoscale
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Figure 1. Microscopic image of various nanoscale units in biology (see Table 1 for details and other examples) (a) Biomembrane. Adapted with
permission from ref 36. Copyright 2003 Springer. (b) Lipid raft at cell membrane. Adapted with permission from ref 54. Copyright 2017 United
States National Academy of Sciences. (c) Clathrin-coated vesicle. Adapted with permission from ref 31. Copyright 2019 Wiley. (d) Microtubules in
live cell. Adapted with permission from ref 57. Copyright 2018 Elsevier. (e) Isolated microtubule. Adapted with permission from ref 39. Copyright
2005 Copyright 2005 American Chemical Society. (f) Iron oxide in magnetotactic bacteria. Adapted with permission from ref 42. Copyright 2006
Springer Nature. (g) Iron oxyhydroxide in iron-oxidizing bacteria. Adapted with permission from ref 34. Copyright 2000 American Association for
the Advancement of Science. (h) Diatom microskeleton. Adapted with permission from ref 37. Copyright 2004 Royal Society of Chemistry. (i)
Amyloid fibril. Adapted with permission from ref 56. Copyright 2017 Elsevier. (j) Superhydrophobic lotus microstructure. Adapted with permission
from ref 33. Copyright 1997 Oxford University Press. (k) Ferritin structure under a physiological condition. Adapted with permission from ref 55.
Copyright 2017 United States National Academy of Sciences. (l) Covid 19. Adapted with permission from ref 60. Copyright 2020 Centers for
Disease Control and Prevention (CDC). (m) Kidney stone microstructure. Adapted with permission from ref 40. Copyright 2016 Nature
Publishing Group. (n) Mineralized bone structure. Adapted with permission from ref 41. Copyright 2006 Wiley. (o) Malaria pigment hemozoin.
Adapted with permission from ref 49. Copyright 2013 Nature Research. (p) DNA helix structure with major and minor grooves of helix. Adapted
with permission from ref 50. Copyright 2015 American Association for the Advancement of Science.

units become integral components. Examples include the
nucleation−growth of calcium phosphate nanocrystals in
bone/tooth38,41 and mineralization of calcium oxalate nano-
particles in kidney stones.40,45 In particular, bone micro-
structures are composed of 10−100 nm platelet-shaped
inorganic crystals intimately mixed with collagen fibrils via
sacrificial bonds that offer good mechanical properties of bone.
Approximately 90% of tooth enamel and dentin is composed of
calcium phosphate nanorods that are 30 nm thick and 60 nm
in length, which provide the required hardness. Deposition of
nano- to micron-sized calcium oxalate (CaC2O4) crystals
around renal epithelial cells of the kidney leads to kidney
stones and necrotic cell death.40 Malaria pigment micro-
structures are formed by malaria parasite-based blood digestion
via conversion of cytotoxic heme units into an insoluble
nontoxic form called hemozoin.49 Hemozoin is an insoluble
microcrystalline form of heme that shows remarkable magnetic
and optical anisotropic properties.
Biomineralized nanounits are also utilized for specific
functions by small animals. For example, magnetotactic
bacteria utilize biomineralized magnetite crystals (Fe3O4) 5−
10 nm in size for navigation in the deep sea using the Earth’s
magnetic field.42 The membrane-enclosed magnetite crystal is
assembled into a linear chain within the bacterium, achieving a
maximum dipole moment that allows navigation along the
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Earth’s magnetic field. Similarly, marine organisms (such as
diatoms/radiolarians) generate porous silica skeletons with
micro/nanostructures using polygonal organic meshwork
templates.32,37 Iron-oxidizing bacteria mineralize 2−3 nm
iron(III) oxyhydroxide particles via a self-aggregated path-
way.34
Nano and microscale architectures have been utilized to
make intelligent surfaces for specific functions. For example,
the double roughness structure of lotus leaves at the nano- to
microscale provides superior water-repellent properties and
self-cleaning ability of the surface, which is commonly known
as the lotus effect.33,51 Solar energy conservation by green
plants requires a nanoscale assembly of chromophoric pigment
molecules for light-induced molecular excitation followed by a
transfer to acceptors.46
3. SIZE-DEPENDENT MATERIAL PROPERTIES AT THE
NANOSCALE WITH BIOMEDICAL APPLICATION
POTENTIAL
Synthetic methods for inorganic- and organic-based varieties of
nanoparticles have been developed, and some of them are
commercially available. Well-known examples are ZnS-capped
CdSe quantum dots, Au/Ag nanospheres, Au nanorods, Ag
platelets, iron oxide nanospheres, dye-doped silica/polystyrene
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Table 2. Selected Examples of Size-Dependent Material Properties along with Their Biomedical Application Potential
nanoparticle size size/shape effect biomedical application potential refs
ZnS-capped CdSe 1−6 nm size-dependent visible emission fluorescent probe 19
Au 2−100 nm size-dependent visible absorption/ optical probe, dark-field contrast agent, surface 61,68
scattering enhanced Raman probe
Au nanorod 5−20 nm diameter, 10−100 length-dependent visible optical probe, dark-field contrast agent, 66,72
nm length absorption/scattering surface-enhanced Raman probe
Ag 2−100 nm size/shape-dependent visible optical probe, dark-field contrast agent, 81
absorption/scattering surface-enhanced Raman probe
iron oxide 1−50 nm size-dependent magnetic property MRI contrast agent, magnetic separation 63,80
dye-doped silica/ 10−100 nm size-dependent colloidal stability imaging/detection probe 65,74−76
polystyrene bead
polymer-coated inorganic 10−200 nm size-dependent colloidal stability cellular imaging/detection probe 67,69−71,78,84
nanoparticle
polymer micelle 10−200 nm size-dependent dispersion stability delivery carrier and in vivo targeting 73,79,83,85−87
Au 1−50 nm size-dependent solvent extraction cell membrane translocation 62,77
carbon nanotube 1−10 nm diameter, nano to length-dependent solvent cell membrane penetration 64
micron length extraction
graphene nano to micron size size-dependent dispersion stability drug delivery 88
and self-assembly

nanobeads, polymer-coated metal/metal oxide nanoparticles,
polymer micelles, carbon nanotubes, graphene, fluorescent
carbon dots, hydroxyapatite nanorods, barium titanate nano-
particles, and upconversion nanoparticles (Table 2 and Figure
2). One important aspect of these nanomaterials is their size-
and shape-dependent properties. Table 2 summarizes the size-
dependent properties of well-known nanoparticles along with
their biomedical application potential.61−88
The most studied class in showing this size effect is
semiconductor nanomaterials, commonly known as quantum
dots, which are made of CdSe-, CdS-, CdTe-, and ZnS-capped
CdSe.19 These quantum dots show size-dependent fluorescent
properties, typically in the size range of 1−10 nm. Figure 3a
shows the size-dependent fluorescent property of colloidal
CdSe nanoparticles in the whole visible spectrum by varying
the particle size from 1 to 6 nm. In particular, the fluorescent
maxima can be varied from blue (400 nm) to red (650 nm) by
increasing the particle size from 1 to 6 nm. This size effect is
due to the increasing gap between the conduction band and
valence band of CdSe as the size decreases, and the particle
size will dictate their light emission property via the relaxation
of excited electrons from the excited state (conduction band)
to the ground state (valence band). Thus, the same blue light
exposure of colloidal solutions of CdSe nanoparticles of
different sizes would show different emission colors, and as the
size decreases, the emission colors will shift from red to blue.82
These quantum dots have unique advantages as bioimaging
probes over molecular probes. They are brighter without any
photobleaching issues under continuous excitation, and they
have a broad excitation window but narrow fluorescence
bands.19,28,82 These properties of quantum dots are used for
single DNA/protein tracking inside cells, imaging of receptors
at the cell surface, and high-resolution imaging of deep tissue.19
Moreover, the fluorescence properties of nanoparticles are
tuned toward the near-infrared (NIR) region to increase the
penetration depth and deep tissue imaging with minimum
background noise.19
Next, a class of nanoparticles that shows size- and shape-
dependent properties are plasmonic nanoparticles that are
commonly made of Au and Ag.18,20 They exhibit intense visible
light adsorption/scattering via a collective oscillation of surface
electrons under light excitation. Figure 3b shows the size-
dependent plasmonic property of colloidal Au nanospheres as
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the size changes from 2.0 to 100 nm. The plasmon band
position of spherical gold nanoparticles can be tuned between
500 and 580 nm by varying the diameter from 5 to 100 nm. In
addition, the plasmon band intensity becomes stronger as the
size increases, but below 3 nm, it becomes very weak. Similar
size-dependent properties are also observed for Ag nano-
particles, and the plasmonic band position of the colloidal
solution can be shifted from 400 to 500 nm with increasing
size from 5 to 100 nm.
The plasmonic property can be tuned much more by
preparing anisotropic Au/Ag nanoparticles.66,72 Figure 3c
shows the optical properties of a colloidal solution of
anisotropic Au nanorods. These nanorods have diameters in
the range of 5−20 nm, lengths in the range of 10−100 nm, and
aspect ratios (length-to-width ratios) in the range of 2.0−18.0.
Gold nanorods exhibit two plasmonic bands: one is a
transverse plasmon band in the range of 500−520 nm (arising
due to plasmonic oscillation along the short axis of the
nanorod), and the other is a longitudinal plasmonic band in
the range of 600−1800 nm (arising due to a plasmonic
oscillation along the long axis of the nanorod). Most
importantly, the longitudinal plasmonic band of the nanorods
can be tuned by varying the nanorod aspect ratio. Similar
variations in optical properties can be made for anisotropic Ag
nanoparticles.81 Figure 3d shows the optical properties of
colloidal solutions of anisotropic Ag nanoparticles with
diameters in the range of 50−100 nm with an aspect ratio
(length-to-width ratio) in the range of 2.0−18.0, and the
plasmonic band can be tuned from 450 to 800 nm by varying
the aspect ratio.81 Optical properties of plasmonic nano-
particles are used as optical probes, dark-field imaging contrast
agents, surface-enhanced Raman spectroscopy (SERS)-based
detection probes, and photothermal therapies.18,20
Another class of nanoparticles that shows size-dependent
properties is magnetic nanoparticles in the size range of 5−50
nm.2,63,80 Magnetic nanoparticles are usually composed of
ferro-/ferri-magnetic materials such as iron, nickel, and cobalt.
They exhibit size-dependent magnetic properties from
ferromagnetic to paramagnetic to super-paramagnetic with
decreasing size. In particular, super-paramagnetism is reported
to arise when ferro/ferromagnetic materials are reduced to a
10−20 nm size, which is due to the parallel alignment of all
magnetic centers along the external field within a small
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Figure 2. TEM image of some well-known nanoparticles showing the
fine control of size in nanoscale. (a) TEM images of three different-
size CdSe-ZnS quantum dots. Adapted with permission from ref 82.
Copyright 2017 Royal Society of Chemistry. (b) TEM images of three
different-size Au nanoparticles. Adapted with permission from ref 61.
Copyright 2003 American Chemical Society. (c) TEM images of Au
nanorods of three different aspect ratios. Adapted with permission
from ref 72. Copyright 2010 Elsevier. (d) TEM images from iron
oxide nanoparticles of three different size. Adapted with permission
from ref 80. Copyright 2017 American Chemical Society. (e) TEM
images of silica nanoparticles. Adapted with permission from ref 74.
Copyright 2012 American Chemical Society. (f) TEM images of
polymer nanoparticles of different sizes. Adapted with permission
from refs 79, 85, and 86. Copyright 2016, 2019, 2020 American
Chemical Society.
magnetic domain.2 The super-paramagnetic nature of ultra-
small iron oxide nanoparticles with a lower relaxivity ratio (r2/
r1) makes them a potential candidate for T1-weighted
contrasting agents in MRI.2 In addition, magnetic nano-
particles can generate heat under a magnetic field, which make
them a potential theranostic agent.2 The heating efficiency of
these magnetic nanoparticles increases with increasing size up
to a certain upper limit. Hence, choosing nanoparticles of
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optimal size is a key factor for the fruitful implementation of
magnetothermal therapy. In addition, magnetic nanoparticles
are combined with an NIR dye or other nanoparticles that can
exhibit high photothermal effects. Thus, near-infrared laser
irradiation can be used for therapeutic applications, and
magnetic resonance imaging-guided photothermal therapy can
be used for tumor ablation.89−93
Another very common size effect is the size-dependent
colloidal stability or dispersion stability, which is quite
common for all types of nanoparticles.70,71,73−76,83,84,87,88 In
particular, colloidal nanoparticles of 5−50 nm in size with
adjusted surface charge or steric stabilization by polymers/
surfactants can be prepared, but greater than 100 nm particles
with good colloidal stability require special attention. For
example, silica nanoparticles exhibit size-dependent dispersion
behavior, and large nanoparticles (>50 nm) tend to aggregate
at a high pH, while the aggregation of small nanoparticles (<50
nm) is slow at low pH.65,74−76 Similarly, the poor colloidal
stability of greater than 100 nm gold nanoparticles, polymer
micelles/nanoparticles, graphene oxide, carbon nanotubes, and
magnetic nanoparticles is well-known. Anisotropic nano-
particles have additional issues, since they can self-assemble
into columnar/smectic phases or form bungle structures
depending on the extent of shape anisotropy.94 However,
nanoparticles of relatively larger size can be prepared using
polymer/stabilizers that offer entropic stabilization.95 In this
case, polymer/stabilizers are used that cannot form an ideal
self-assembled monolayer around the nanoparticle surface, and
the disordered structure would compensate for some of the
translational entropy loss via a localized free movement of the
branches, offering more interaction with the solvent. For
example, hydrophobic iron oxide nanoparticles greater than 10
nm in size are difficult to prepare using stearic acid as the
capping ligand, but 20−40 nm iron oxide nanoparticles can be
prepared using oleic acid as the capping ligand.29 Although
both stearic acid and oleic acid have 18 hydrocarbon chains, an
unsaturated double bond is present in oleic acid that inhibits
the compact monolayer structure around nanoparticles and
induces an entropic stabilization. Similarly, branched ligands
are used to prepare colloidal hydrophobic nanoparticles greater
than 10 nm in size.95
The size effect on colloidal stability also plays a significant
role in the synthesis of monodispersed nanoparticles. In
addition, size-dependent colloidal stability has been utilized in
the size-selective separation of nanoparticles and size-depend-
ent solvent extraction of nanoparticles62,64,77 (Figure 4). For
example, the synthesis of high-quality monodispersed nano-
particles (e.g., quantum dots, iron oxide, Ag) in organic phases
is limited in the size range of 1−20 nm, and the synthesis of
larger particles is unsuccessful due to a poor colloidal stability.
Here, the colloidal stability of nanoparticles is due to the
hydrophobic capping ligands that allow a solubilization of
nanoparticles in the organic phase, but as the core size
increases, the solubility of nanoparticles decreases. However,
larger nanoparticles can be solubilized in organic solvents by
designed ligands that offer the entropic stabilization described
above. This size-dependent solubility of nanoparticles is used
in the size separation of selected sizes from mixed sizes.62,77
Typically, a bad solvent is gradually added to a nanoparticle
solution, and larger nanoparticles first precipitate from
solutions that are isolated. A similar approach is utilized in a
size/length-dependent solvent extraction of nanoparticles64
(Figure 4). For example, small (<10) Au nanoparticles can be
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Figure 3. Size- and shape-dependent optical property of various nanoparticles. (a) Digital image of colloidal solutions of quantum dots of six
different sizes under UV excitation and their size-dependent fluorescence spectra. Adapted with permission from ref 19. Copyright 2017 Springer
Nature. (b) Digital image of colloidal solutions of spherical Au nanoparticles of different sizes and their size-dependent absorption spectra. Adapted
with permission from ref 68. Copyright 2007 American Chemical Society. (c) Digital image of colloidal solutions Au nanorods with the length to
width (aspect ratio, AR)-dependent absorption spectra. Adapted with permission from ref 72. Copyright 2010 Elsevier. (d) Digital image of
colloidal solutions of Ag nanoprisms of different sizes and their absorption spectra. Adapted with permission from ref 81. Copyright 2017 American
Chemical Society.

easily extracted from the aqueous to an organic phase via a
hydrophobic surfactant/polymer capping, but larger nano-
particles stay in the aqueous phase. Here, smaller nanoparticles
have a higher surface-to-volume ratio, and the hydrophobic
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surfactant coverage is high enough to extract/solubilize them
in the organic phase compared to larger nanoparticles. This
size effect is further modified for anisotropic Au nanorods,
graphene, and carbon nanotubes, and relatively larger particles
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Figure 4. Nanoparticle size and shape effect on solvent extraction via a hydrophobic surfactant capping. (a) Schematic representation of
nanoparticle size and shape effect in solvent extraction showing that nanospheres of less than 10 nm size and shorter nanorods of less than 30 nm
length with less than an 8 nm short axis can be extracted into an organic phase, but larger particles aggregate during extraction. (inset) Different
nanoparticles of less than 10 nm that are extracted into an organic phase. (b) Solvent extraction of CTAB-capped Au nanospheres and nanorods
from an aqueous (bottom) to an organic toluene (upper) phase via formation of ion associates with decanoic acid, showing the successful
extraction of only smaller spheres/nanorods. (i) 4 nm sphere, (ii) 8 nm sphere, (iii) 12 nm sphere, (iv) nanorod of 6 × 15 nm, (v) nanorod of 8 ×
30 nm, (vi) nanorod of 10 × 40 nm. (c) Length-dependent phase transfer of carbon nanotube showing that longer nanotubes are easier to extract
with increasing extractant concentration. Adapted with permission from ref 64. Copyright 2005 American Chemical Society.

Scheme 2. Basic Principles of Fine Control of Nanoparticle Size in the 1−100 nm Range Via Most Advanced Colloid-Chemical
Approachesa

a
Size control of quantum dots is achieved in the 1−10 nm range via a high-temperature-controlled nucleation−growth (I), size control of metal/
metal oxide nanoparticle in the range of 2−100 nm is achieved via a similar controlled nucleation−growth (II), size control of metal nanoparticle in
the range of 1−15 nm is achieved via an arrested nucleation by a strong capping ligand followed by a digestive ripening/Ostwald ripening (III), and
a size control of different nanoparticles in the range of 5−100 nm is achieved via a seeding growth approach (IV).

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Scheme 3. Basic Approaches of Transformation of as-Synthesized Nanoparticle into Functional Nanoparticle Via Surface
Chemistry and Conjugation Chemistrya
a
Exchange with hydrophilic ligand or polymer can be adapted for nanoparticles of different type/size, and polymer coating can be used to control
the overall size via a thin/thick polymer shell. Conjugation chemistry can be adapted with a coated nanoparticle using chemical functional groups at
the particle surface.
can be extracted, since they have a higher surface-to-volume
ratio for ligand coverage.64 This size effect is relevant for the
cellular uptake of nanoparticles, where nanoparticles are
transferred/extracted from the aqueous phase to the organic
phase, such as the cell membrane, or the biomineralization of
inorganic components occurring at biological interfaces.28,44
4. PREPARATION OF NANOSCALE ARCHITECTURES
FOR BIOMEDICAL APPLICATION
4.i. Synthesis of Various Nanomaterials of Controlled
Size and Shape. The synthesis of nanomaterials is broadly
classified into two routes: top-down and bottom-up
approaches. In the top-down approach, bulk materials are
sliced apart into nanosized materials via various mechanical
processes, for example, ball milling, grinding, and lithog-
raphy.96 However, this approach lacks a precise control of the
shape, size, and uniformity of the synthesized nanomaterials. In
the bottom-up approach, atoms and molecules assemble in a
controlled manner to produce nanomaterials.9−11,61,63,96−98
This technique involves the collision of atoms/molecules,
leading to a nucleation−growth and formation of nanomateri-
als. The bottom-up approach primarily involves various
solution-phase syntheses, and this approach is extensively
adopted for biomedical applications, since it offers distinct
advantages in controlling the size, shape, and uniformity/
monodispersity.
The size-controlled synthesis of metal and semiconductor
nanoparticles via a solution phase synthesis is the most
advanced.29 Basic principles in the fine control of particle size
are summarized in Scheme 2. Noble metal nanoparticles such
as gold, silver, platinum, and palladium are prepared through
the reduction of the respective metallic salts in the presence of
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various surfactants or capping agents. Size control was achieved
by controlling the nucleation−growth condition. Historically, a
citrate reduction of gold salt in boiling water has been the most
famous and still used method in controlling gold nanoparticle
sizes between 10 and 100 nm.99 Here, citrate acts as both a
capping and reducing agent, and the size can be controlled by
varying the citrate concentration. An uncontrolled nucleation
associated with a rapid growth of nucleation is most common
in the metal salt reduction approach, and thus, any attempt to
make larger nanoparticles (>10 nm) via a one-step reduction
eventually results in a polydispersed size distribution.100 In a
practical approach, smaller size (<5 nm) metal nanoparticles
are prepared by arresting early nucleation by using strong
capping ligands/polymers. The well-known example is the
Brust method, where a thiol-based surfactant is used as the
capping ligand.101 Larger nanoparticles in the size range of 5−
50 nm with ultranarrow size distributions are prepared via
digestive ripening or seeding growth approaches. In the
digestive ripening approach, surfactant-capped nanoparticles
are heated at selected temperatures to allow Ostwald ripening,
and smaller particles or anisotropic particles grow at the
expense of larger spheres. Following this approach, high-quality
near-monodispersed nanoparticles in the size range of 5−10
nm can be prepared depending on the temperature and
capping surfactant.102 In the seeding growth approach, smaller
nanoparticles are used as preformed nucleation centers (seeds)
and allowed to grow in a specified growth medium.103 With
this approach, near-monodispersed nanoparticles of different
types in the size range of 5−50 nm can be prepared.61,104
The synthesis of semiconductor nanoparticles is performed
via a high-temperature colloid-chemical approach, and the
particle size is controlled in the size range of 1−10 nm by
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controlling the nucleation and growth.105,106 A well-known
example is the synthesis of CdSe nanoparticles, where the Se
precursor is injected into a hot solution of the Cd precursor to
nucleate CdSe particles. Next, the growth of CdSe is stopped
within a few seconds/minutes via a rapid cooling of the
solution. Depending on the growth time, CdSe of different
sizes in the range of 1−6 nm is formed. This approach of size
control has been adapted for other semiconductor nano-
particles, such as CdS, CdTe, ZnS, ZnSe, and PbSe.
Similarly, metal oxide (Cr, Mn, Fe, Cu, Ni, Ti) nanoparticles
are synthesized by a high-temperature decomposition of the
respective fatty acid salts. Here, nanoparticle size control has
been achieved by using long hydrocarbon chain fatty acids/
amines of different molar ratios and by varying the chain
lengths of the hydrocarbons.10,63,107 Long-chain fatty acids/
amines act as capping agents as well as solvents, and
nucleation−growth is controlled by varying the temperature
and acidic/basic conditions. Near-monodispersed iron oxide
and other oxide nanoparticles in the size range of 5−30 nm can
be prepared by this approach.107,108
The synthesis of other well-known nanoparticles includes
silica particles in the size range of 20−100 nm and various
polymer nanoparticles in the size range of 50−200 nm. Silica
nanoparticles are prepared via the Stöber approach with the
hydrolysis of silane precursors, and the particle size is
controlled by the reaction time, capping with the selected
ligand, and varying the reaction conditions.75,109 Poly(lactide-
coglycolide) (PLGA) nanoparticles are prepared via restricted
precipitation and stabilization approaches.110 Typically, a
chloroform solution of the PLGA polymer is injected in an
aqueous surfactant solution under vigorous stirring to form a
microemulsion, and the successive evaporation of chloroform
microdroplets leads to the formation of surfactant-stabilized
PLGA nanoparticles.
A shape-controlled synthesis of nanoparticles utilizes a
further manipulation of nucleation−growth conditions. The
most widely known gold nanorods of varied length are
prepared via a seeding growth approach, where small spherical
gold seeds (<3 nm) are grown in the presence of gold
precursors and surfactants.111 Here, the role of the surfactant is
to cap the side faces and allow growth in one dimension. The
length of the nanorods is controlled by varying the seed to gold
salt and other conditions. This approach has been used to
prepare gold nanorods with short axes of 5−10 nm and lengths
between 10 and 100 nm. Silver platelets/nanorods/nanowires
and CdSe/TiO2/hydroxyapatite nanorods are prepared by
seeding growth, accelerated growth, or manipulating growth
conditions.29,81,112,113
4.ii. Surface Chemistry, Ligand Modification, Bio-
conjugation Chemistry. Biomedical applications require the
transformation of as-synthesized nanoparticles into water-
dispersible and functional nanoparticles.29 Basic approaches for
such a transformation involve surface chemistry and con-
jugation chemistry, as summarized in Scheme 3. There are
three specific reasons for this transformation. First, nano-
particles interact with biological interfaces using their surface
chemical groups, and the appropriate functional groups at the
nanoparticle surface would allow such interactions. However,
most of the as-synthesized nanoparticles are terminated with
ligands or polymers that might not be ideal for interaction.
Second, a colloidal dispersion of nanoparticles in water is
essential for their accessibility and interaction with biological
interfaces. The reason is mostly because intra- and extracellular
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spaces are filled with water, and nanoparticles need to travel to
the required destination to interact. However, most of the
high-quality nanoparticles that are synthesized via advanced
approaches are water-insoluble. Moreover, many commercially
available nanoparticles are nondispersible in water. Third,
nanoparticles should have an adequate colloidal stability during
interactions with biological interfaces. This criterion is
especially important because the biological environment is a
complex mixture of high amounts of salt and various polymers
of anionic/cationic charges. In contrast, the colloidal stability
of nanoparticles relies on the surface charge, and the presence
of high salt conditions or oppositely charged polymers can
induce particle aggregation/precipitation.
Ligand exchange and polymer-coating chemistry are
routinely adapted for such transformation processes.29 In the
ligand exchange approach, the original capping ligand is
replaced by the desired ligand based on the chemical affinity of
the ligand with the nanoparticle surface. In particular, thiol-
based surfactants/polymers are used to replace the original
ligand at the surface for noble metal nanoparticles, because
thiols have a good chemical affinity with noble metals.29 In
addition, catechol-based ligands are used for the exchange of
surfactants from the metal oxide nanoparticle surface,114 and
polythiol-based ligands are used to replace the original ligands
from the semiconductor nanoparticle surface.71,115 In the
polymer coating approach, nanoparticles are coated with
polymers via a partial or complete exchange of the original
capping ligands.19,29,71 Well-known examples include poly-
(maleic anhydride) coating, polyacrylate coating, and silica
coating.19,29,71 In poly(maleic anhydride) coatings, hydro-
phobic nanoparticles and polymers are mixed together to allow
a hydrophobic encapsulation of polymer hydrophobic chains
with hydrophobic ligand shells. Next, polymer-coated nano-
particles with surface-terminated anhydride groups are reacted
with basic water or amine-based chemicals. In the silica/
polyacrylate coating approach, nanoparticles are exposed to
silane/acrylate monomers, and the polymerization of silane/
acrylate is initiated at the nanoparticle surface. With these
polymer coating approaches, a cross-linked polymer shell with
a high colloidal stability of nanoparticles can be prepared.29
The hydrodynamic size, which includes both core nano-
particles and the outer shell, will depend on the core
nanoparticle size and the shell thickness. In particular, the
shell thickness can be varied from 5 to 50 nm by adjusting the
coating condition, and water-soluble nanoparticles with
hydrodynamic sizes in the range between 10 and 100 nm
can be prepared.17,29
Colloidal nanoparticles with ligand/polymer shells can be
further modified with biochemicals via a wide variety of
conjugation chemistry.17,29 In this case, chemical functional
groups present at the nanoparticle surface and biochemical
functional groups can be used for conjugation chemistry. In
particular, 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide
(EDC)-based coupling chemistry, N-hydroxysuccinimide
(NHS) reagent-based conjugation chemistry, and maleimide
reagent-based conjugation chemistry are widely used.29
Following these approaches, a wide variety of water-dispersible
functional nanoparticles and nano-bioconjugates are prepared
that are cationic/anionic/zwitterionic and terminated with
vitamin/carbohydrate/peptide/antibody.17,29
4.iii. Toxicity, Biocompatibility, and Biodegradability
Issues. When nanoparticles are designed for biomedical
applications, the toxicity and biocompatibility of the nanoma-
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Figure 5. Effect of Au/Ag nanoparticle size on plasmonic band and SERS. (a) Size effect of Au nanoparticle plasmonic band in colloidal form (1) vs
aggregated form in the presence of salt (2) that is important for the SERS signal. Digital image shows colors of colloidal solutions that changes most
significantly for 12 nm Au. (b) SERS signal of 100 nM mercaptopyridine (in the presence 0.1 M NaCl that agglomerates Au nanoparticles) showing
the particle size effect. (c) Au and Ag nanoparticle size effect in the SERS-based detection limit of mercaptopyridine, showing that 20−70 nm is the
best size. Adapted with permission from ref 129. Copyright 2007 Wiley.
terials should be considered carefully.12,116−119 This consid-
eration is especially important because a smaller size can offer
an easier option to interact with biological interfaces via an
easier migration, mild toxicity issues can lead to adverse
biological effects due to excessive exposure, large-scale use of
materials could invite environmental pollution, and any human
application requires insignificant toxicity. The toxicity of
nanoparticles arises primarily for four specific reasons. First,
toxic materials are used to make nanoparticles, and thus, it is
expected that nanoparticles would be toxic via the release of
toxic components to the bioenvironment. Examples are toxic
cadmium-based semiconductor nanoparticles, toxic lead-based
nanoparticles, and other heavy metal-based nanoparticles.
Second, the surface properties of nanoparticles can dictate
the toxicity. In particular, cationic or cationic-lipophilic
nanoparticles are usually more toxic than anionic nanoparticles,
because cationic/lipophilic properties offer an interaction with
the cell membrane more strongly. For example, nontoxic gold
nanoparticles can be made toxic via a conjugation with cationic
ligands, and quantum dots can be more cytotoxic due to the
cationic surface charge.71,120 Third, the nanoparticle size can
dictate the toxicity. In particular, a larger particle size (>100
nm) with poor solubility inhibits their interaction with the
biological environment and thus lowers the toxicity. Examples
include the size-dependent toxicity of mesoporous silica
nanoparticles121 and silver nanoparticles.122 Fourth, the
physical environment and biochemical conditions can induce
toxicity. For example, nontoxic iron oxide nanoparticles can
apparently be toxic under an intracellular environment in the
presence of intrinsic hydrogen peroxide,15,123 and semi-
conductor nanoparticles can be more toxic under light
exposure via photochemical reactions. Recent studies also
show that poly(ethylene glycol) (PEG)-coated silica nano-
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particles can stimulate the immune system and lead to
ferroptosis with a programmed cell death.124
Thus, nanoscale functional materials are designed with four
specific aspects to minimize the toxicity issue.1−3,17,29 First, in
vivo applications of nanoscale materials are preferably designed
with biocompatible and biodegradable materials. Well-known
examples are PLGA nanoparticles, lipid-based vesicles, and
chitosan-based nanoparticles that are used as drug delivery
carriers. Second, nanoparticles are terminated with an
appropriate surface chemistry that minimizes the cationic
surface charge and are coated with nontoxic materials.17,29 The
most common example is to conjugate nanoparticles with PEG
or dextran. Third, toxic nanoparticles are capped with nontoxic
materials to avoid toxicity. Examples include capping the CdSe
with less-toxic ZnS or the coating of toxic nanoparticles with
silica.71 Fourth, in vivo applications of nanomaterials are
designed in such a way that they are either excreted after the
intended performance or degraded biologically.
5. NANOBIO INTERFACE: EXPLORING THE
NANOPARTICLE SIZE EFFECT IN DIFFERENT
BIOMEDICAL APPLICATIONS
In biomedical applications, a variety of nanoparticles are
designed to interact with different biological interfaces, such as
proteins, DNA, cell membranes, cell junctions, subcellular
compartments, tissues, lungs, kidneys, skin, and blood-brain
barriers. During these interactions, the nanoparticle size plays
an important role in various ways, depending on the nature of
the biological interface and the application type.125−149 Here,
we divide all of these size effects into four specific contexts.
First, there are biosensing and bioimaging applications, where
the nanoparticle size preference is primarily guided by size-
dependent material properties. Second, cellular uptake
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Figure 6. Gold nanoparticle size effect in a colorimetric detection of an oligonucleotide. (a) Schematic representation of gold nanoparticle
aggregation-based colorimetric detection of oligonucleotide using two different approaches. (b) Shift of UV−visible absorption spectra during an
aggregation-based detection of DNA by an oligonucleotide-conjugated gold nanoparticle. (inset) Solution color change during the detection. (c)
Shift of UV−visible absorption spectra of gold nanoparticle of different sizes in the presence of a target. Larger nanoparticle (50 nm) exhibits a
higher peak shift and better limit of detection. Adapted with permission from ref 144. Copyright 2016 American Chemical Society.

Table 3. Selected Examples of the Size Effect of a Functional Nanoparticle toward Different Biomedical Applications
nanoparticle (size) functional groups at surface application size effect refs
Au/Ag (2−50 nm) oligonucleotide/antibody DNA/protein <10 nm is better for labeling probe but larger size is better for optical 131,143,144
detection detection
Au/Ag (5−100 nm) dye/biomolecule surface-enhanced size-dependent surface-enhanced Raman sensitivity and larger size is 125,129
Raman biosensor better
Au nanorod, Ag platelet surfactant/oligonucleotide biosensor anisotropy dependent detection sensitivity and self-assembly 94,129
(10−100 nm)
iron oxide (1.5−12 nm) PEG T1MRI contrasting smaller size is better 134
agent
Fe3O4 nanoparticle herceptine antibody T2MRI contrast larger size is better 127
(4−12 nm) agent
quantum dot (5−50 nm) sugar amphiphile cellular endocytosis enhanced endocytosis with increased size 126
Au (10−100 nm) citrate cell uptake 50 nm has faster uptake than smaller or larger one 128
Au nanoparticle (2−70 herceptin cellular endocytosis enhanced endocytosis with increased size 130
nm)
Au (15−150 nm) mercaptoundecanoic acid computed 50 nm/75 nm particle exhibits higher monocyte uptake 147
tomography
imaging
Au (2.4−89 nm) PEG, peptide subcellular trafficking size effect in subcellular trafficking 135
Au nanoparticle (2−10) mercaptoundecanesulfonate cell uptake <2.5 nm is critical for membrane insertion of anionic particle 136
and octanethiol
Au (6−50 nm) arginine cell uptake direct membrane translocation for <10 nm but endocytic uptake for > 149
10 nm
Au (10−100 nm) PEG tumor targeting 100 nm particle accumulate perivascular space while 20 nm particle 132
exhibit higher tumor penetration
quantum dot (10−150 silica fluorescence imaging 12 nm particle have higher circulation time, tumor penetration and 133
nm) probe extravasation than 60/125 nm particle
Au (15−100 nm) PEG, transferrin tumor targeting 30 and 60 nm particle shows enhanced active delivery 140
polymer micelle amphiphilic block copolymer drug delivery carrier higher tumor accumulation for 100−160 nm micelle due to longer 141
(20−300 nm) circulation but higher penetration by 30 nm micelle
zeolite-imidazolate poly(allylamine drug delivery for prolong circulation and tumor uptake by 60 nm particle 148
framework (30−120) hydrochloride) cancer therapy
Au nanorod/nanosphere PEG photo thermal size-dependent heat generation under light irradiation 137,139
(20−50 nm) therapy
iron oxide (6−40 nm) PEG thermoablative heat generation increases with size 80
therapy
Au (2−40 nm) glutathione inhibition of amyloid smaller particle are better 146
fibrillation

processes and subcellular targeting occur, where the nano-
particle size preference is primarily guided by the properties of
biological components. Third, there is in vivo targeting and
imaging, where the nanoparticle size preference is required to
obtain the correct material properties along with their
biophysical processing. Fourth, biomedical therapy with
nanoparticle size selection is important to utilize the size-
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dependent material properties associated with their biological
processing.
5.i. Nanoparticle Size Effect in Biosensing and
Bioimaging Applications. In biosensing and bioimaging
applications, the optical properties of nanoparticles are often
used for detection/imaging applications. Because the optical
properties of nanoparticles are size-dependent, the detection/
imaging application of such nanoparticles requires an
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Figure 7. Iron oxide nanoparticle size effect in MRI imaging. (a) (i) TEM image of Fe3O4 nanoparticles of 4−6, 9, and 12 nm diameter. (ii) Size-
dependent T2-weighted MR images of Fe3O4 nanoparticle in aqueous solution at 1.5 T. (iii) Size-dependent color-coded MR images based on T2
values that change from red to blue. (iv) Size-dependent change in T2 value and field-dependent magnetization curve of an Fe3O4 nanoparticle.
The results show that the efficiency of an Fe3O4 nanoparticle as T2-weighted MRI contrasting agent increases from 4 to 12 nm. (v) T2-weighted
MR images of breast cancer cell pellets treated with a herceptin-conjugated Fe3O4 nanoparticle of diameter 12 nm. Adapted with permission from
ref 127. Copyright 2005 American Chemical Society. (b) (i) Field-dependent magnetization curves at 300 K for iron oxide nanoparticles with
diameters of 1.5, 2.2, 3, and 12 nm. (ii) Fe concentration-dependent change in 1/T1 value of iron oxide nanoparticles of 2.2, 3, and 12 nm size
showing that the efficiency as T1-weighted contrast agent increases as size decreases. (iii) T1-weighted MR images of MCF-7 cell pellets using iron
oxide nanoparticles of 3 and 12 nm, showing that the 3 nm size exhibited a better contrast enhancement. Adapted with permission from ref 134.
Copyright 2011 American Chemical Society.

appropriate size. In particular, the plasmonic properties of
individual Au/Ag nanoparticles become more intense with
increasing particle size from 2 to 100 nm.18,20 Moreover, the
color of Au/Ag nanoparticle aggregates depends on the particle
size.20 Thus, all optical detections that use colors of Au/Ag
nanoparticles become size-dependent. For example, a Au
nanoparticle-based colorimetric detection of oligonucleotides
that utilizes the color of the aggregated nanoparticles is size-
dependent, and larger nanoparticles (50 nm) exhibit a higher
peak shift and a better limit of detection125,129,131,143,144
(Figures 5 and 6 and Table 3). Typically, a Au/Ag
nanoparticle-based colorimetric detection of oligonucleoti-
des/antibodies utilizes a < 10 nm probe for efficient labeling
but uses larger nanoparticles (via the enlargement of small
nanoparticles) for a better optical detection.131,143,144 Similarly,
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for an SERS-based detection of biomolecules that utilizes the
optical properties of colloidal aggregates of Au/Ag nano-
particles, 20−70 nm appears to be the optimum size125,129
(Figure 5).
Au/Ag nanoparticles are used as contrast agents in dark-field
microscopic imaging, where scattered light from nanoparticles
is used for imaging. Because the scattered light intensity
increases with the particle size and the nature of the scattered
light depends on the particle composition/shape, larger
particles are used for a better contrast, and different types of
nanoparticles are used for varied colors.20 Moreover, smaller
nanoparticles are used for efficient labeling without steric
hindrance, and then, the small particles are grown to larger
sizes to obtain enhanced scattering signals.131
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Figure 8. Nanoparticle size effect in endocytotic cell uptake processes. (a) Schematic representation of nanoparticle size effect in different types of
endocytosis. (b) Schematic representation (i) and experimental results (ii) of nanoparticle size effect in receptor-mediated endocytosis. ErbB2
receptor overexpressed breast cancer cell is treated with herceptin-conjugated gold nanoparticle of 2 (left), 40 (middle), and 70 (right) nm
diameter followed by a fluorescence imaging. Result shows that nanoparticles of 40 nm diameter enter into cytosol, while 2 and 70 nm
nanoparticles reside on the cell membrane. Scale bars represent 10 μm. Adapted with permission from ref 130. Copyright 2008 Nature Publishing
Group. (c) Nanoparticle size effect in subcellular delivery/trafficking of Au nanoparticles of different size (2.4, 8.2, 16 nm) conjugated with cell-
penetrating peptide showing that nanoparticles with a 2.4 nm diameter localize into the nucleus (left), 8.2 nm localize at a perinuclear region
(middle), and 16 nm reside on a cell membrane (right). Adapted with permission from ref 135. Copyright 2011 American Chemical Society.

The magnetic property of iron oxide nanoparticles is used as
an MRI imaging contrast agent.2 Since the magnetic property
of nanoparticles depends on the particle size, the particle size
dictates the type of contrast agent (T1-weighted or T2-
weighted) and the imaging sensitivity127,134 (Figure 7). For
example, the T2-weighted MRI contrasting property increases
from 4 to 12 nm. However, the efficiency as the T1-weighted
contrast property increased as the size decreased, and a 3 nm
size exhibited a better contrast enhancement. As a T1 contrast
agent, the surface sites are primarily responsible for inducing
relaxation, and smaller nanoparticles with a higher surface-to-
volume ratio offer a larger number of surface sites. Thus, the
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relaxation becomes higher for smaller nanoparticles, which
makes them better T1 contrast agents than larger nano-
particles. As a T2 contrast agent, the magnitude of the
magnetic spin of the nanocrystal induces a spin−spin
relaxation. Since the magnitude of this mass magnetization
increases with size, a larger size is responsible for a better
magnetic contrast.
5.ii. Nanoparticle Size Effect on Cellular Uptake
Processes and Subcellular Targeting. The cellular and
subcellular targeting of drugs is critical for their effective
performance. This finding is important because most of the
drugs act at the cellular/subcellular level, but reaching that
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Figure 9. Nanoparticle size effect in endocytosis vs direct membrane permeation and its impact on the cell delivery of protein. (a) Schematic
representation of the size effect of arginine-terminated Au nanoparticles in a direct membrane penetration vs endocytosis and its impact on
nanoparticle-mediated cytosolic protein delivery. An ∼6 nm size is able to deliver protein to cytosol via a direct translocation, while 18 nm/45 nm
nanoparticles are unable to do so. (b) Nanoparticle size effect for a BSA delivery to a HeLa cell using arginine-terminated Au nanoparticles via an
electrostatic assembly. Result shows a rapid nuclear delivery of BSA by 6 nm Au, but larger nanoparticles are unable to deliver BSA to nucleus.
Adapted with permission from ref 149. Copyright 2020 American Chemical Society.

target is limited, for various reasons. Some of the issues include
the poor water solubility of drugs, poor cell membrane
permeation, rapid clearance from cells via cellular machinery,
or rapid blood clearance. Recently, the nanoformulation of
drugs or nanocarrier-based drug delivery has become an
important research focus for solving some of these
issues.1,3,13,14,16 These effective formulations consider deliver-
ing drugs to cell/subcellular compartments, where the
nanoparticle size plays a leading role. There are four specific
reasons for the nanoparticle size effect on cellular uptake
processes and subcellular targeting. First, cells use endocytotic
processes for the uptake of foreign materials, and these
processes involve membrane wrapping around foreign
materials followed by pinching a part of the membrane and
the formation of endocytic vesicles. Membrane wrapping/
bending is restricted for hard materials less than 10 nm in size
or extremely soft nanoparticles due to the high energy
cost.150,151 Thus, an endocytic uptake of material is often
restricted to a < 10−20 nm size, and the uptake increases with
increasing size in the 10−100 nm range.126,128,130,147 Second,
the size of the endocytic vesicles varies in the range of 50−100
nm, depending on the type of endocytosis; thus, the
nanoparticle size can direct the type of endocytosis. Moreover,
endocytosis is generally restricted to micron-sized particles.35
Third, a nonendocytic entry or the direct membrane
penetration of materials depends strictly on having a smaller
size (<10 nm where endocytosis is restricted) along with a
specific surface chemistry (arginine termination that specifi-
cally interacts with the cell membrane) or temporary
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membrane deformation of the cell membrane via a
chemical/physical stimulation.149,150 Fourth, the subcellular
targeting efficiency of foreign material depends on the particle
size.135 The reason is that a clathrin-mediated uptake of
cationic/hard/larger particles leads to trafficking to endo-
somes/lysosomes with limited subcellular targeting. In
contrast, a nonendocytic entry, direct membrane penetration,
or lipid raft-mediated uptake of smaller/softer material allows a
cytosolic delivery of material with limited vesicular trapping,
which can be used for subcellular targeting.149
Table 3 and Figures 8 and 9 highlight these size effects. For
example, a receptor-mediated uptake of nanoparticles of
different sizes shows that 40 nm has an endocytic uptake
into the cytosol, while 2 and 70 nm particles reside on the cell
membrane.130 A similar type of size effect is observed in the
endocytic uptake of sugar-terminated quantum dots and
ligand-stabilized Au nanoparticles. Moreover, cell-penetrating
peptide-functionalized Au nanoparticles show a nuclear
localization at a 2.4 nm size, perinuclear localization at a 8.2
nm size, and membrane residence at a 16 nm size.135 Here, a
cell-penetrating peptide termination offers the entry of
nanoparticles into cells, and the particle size dictates their
entry into the nucleus by crossing the nuclear membrane pore
or perinuclear localization without crossing the membrane. In
particular, a smaller size of less than 5 nm will cross the nuclear
membrane and localize inside the nucleus, but larger
nanoparticles will localize outside the nuclear membrane.
Moreover, the nanoparticle size effect is observed in an
endocytosis versus direct membrane permeation (Figure 9).
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Figure 10. Nanoparticle size effect in in vivo targeting and renal clearance. (a) Schematic representation of fine microstructure of kidney showing
the ideal size of particle to pass through the glomerular filter pore of <6 nm. Adapted with permission from ref 138. Copyright 2013 Elsevier. (b−d)
Size-dependent excretion, blood half-life, and in vivo biodistribution of nanoparticles. Under the threshold of 5 nm, injected nanoparticles are
rapidly filtered and excreted by the kidneys. When the diameter is up to hundreds of nanometers, nanoparticles accumulate within the lung, spleen,
and liver. In the size range of 20−150 nm, nanoparticles also accumulate in a tumor (if present) by the EPR effect. Adapted with permission from
ref 145. Copyright 2015 Nature Publishing Group.

For example, a direct membrane penetration by arginine-
terminated nanoparticles is possible for particles less than 10
nm in size, but as the size increases, they enter via an
endocytosis.149 This size effect is further reflected when they
are used as cell-delivery carriers. While 6 nm nanoparticles are
able to deliver proteins to the cytosol or cell nucleus via a
direct translocation, 18 nm/45 nm nanoparticles are unable to
do so.
5.iii. Nanoparticle Size Effect for In Vivo Targeting
and Imaging. In vivo targeting applications of nanoscale
materials commonly involve an intravenous injection of
materials. These applications require the design of an
appropriate material size for an enhanced bioavailability in
actual sites. This aspect is important because these nanoma-
terials must travel from the injection site to the required site
via blood circulation for their effective performance. Such a
targeting is particle-size-dependent for two specific reasons.
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First, the colloidal stability of the nanoparticles decreases with
increasing size, and typically, inorganic nanoparticles greater
than 100 nm in size and organic nanoparticles greater than 500
nm in size have a low dispersion stability. Thus, any larger
materials with a low colloidal stability precipitate near the
injection size and are unable to travel further.62,64,74,77 Second,
injected nanoparticles can be rapidly excreted via the kidney if
the size is less than 5 nm. The reason is due to the size limit of
the glomerular filter pore of the kidney, which is typically in
the range of 2−8 nm. In addition, the surface chemistry,
biochemical stability, and particle shape collectively influence
this size effect.138,142 For example, rod- or wire-shaped
nanoparticles have a better in vivo targeting performance
than spheres of similar size, because they can remain in the
bloodstream for a longer time by aligning along the blood
flow.141 Charged nanoparticles or toxic nanoparticles induce an
immune response for rapid blood clearance via the
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Figure 11. Nanoparticle size effect in magnetothermal therapy and photothermal therapy. (a, b) Effect of iron oxide nanoparticle size in
thermoablative therapy for in vivo tumor heating. Adapted with permission from ref 80. Copyright 2017 American Chemical Society. (c) Variation
of photothermal efficiency as a function of diameter of the Au nanoparticle. Adapted with permission from ref 137. Copyright 2013 American
Chemical Society. (d) Photothermal efficiency of Au nanorod as a function of aspect ratio. Adapted with permission from ref 139. Copyright 2014
American Chemical Society.
reticuloendothelial system (e.g., the liver and spleen). Thus,
nanomaterials are often surface-terminated with PEG or
carbohydrate to minimize such a clearance.29 Figure 10 and
Table 3 highlight such a size effect as an example; they show
that injected nanoparticles of less than 5 nm size are rapidly
excreted by the kidneys, but sizes up to 100 nm accumulate
within the lung, spleen, and liver.
Most importantly, this size effect has been utilized for
indirect tumor targeting. Leaky tumor blood vessels offer an
enhanced permeability and retention (EPR) effect that allows
an enhanced accumulation of nanoparticles in the size range of
20−150 nm. Thus, a wide variety of molecular drugs are
designed with nanoformulations for in vivo tumor targeting via
the EPR effect. Examples include PEG-terminated Au
nanoparticles for tumor therapy, silica-coated quantum dots
for tumor imaging, transferrin and PEG-conjugated Au
nanoparticles for enhanced tumor delivery, and polymer
micelle-based drug delivery to the tumor site.132,133,140,141,148
In addition to this passive targeting, nanodrugs have been
designed for the combination of active and passive
targeting.1,3,13,14 In these designs, nanoparticles of appropriate
size are encapsulated with molecular drugs, and the surface is
terminated with affinity biomolecules. The appropriate size
allows tumor targeting, and an appropriate surface function-
alization allows entry into cancer cells.
5.iv. Nanoparticle Size Effect in Biomedical Therapy.
Nanoscale materials are used in a wide variety of therapeutic
applications, including cell therapy, tumor therapy, and organ
therapy. The approaches involve magnetic nanoparticle-based
magnetothermal therapy, plasmonic nanoparticle-based photo-
thermal therapy, semiconductor nanoparticle-based photo-
dynamic therapy, molecular drug-based nanoformulation for
cancer therapy, reactive oxygen species (ROS)-generating
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nanoparticle-based cell therapy, piezocatalytic nanoparticle-
based sonodynamic therapy, and a nanoparticle-based
inhibition of amyloid aggregation.1,3,8,12,14,15 Table 3 summa-
rizes these size effects, and Figures 11−13 highlight some
selected examples.
In these biomedical applications, the nanoparticle size plays
roles mainly in three different ways. First, the nanoparticle size
dictates the material properties that are responsible for
magnetothermal therapy or photothermal therapy. For
example, a thermoablative therapy for an in vivo tumor
heating performance increases with the increased size of iron
oxide nanoparticles from 6 to 40 nm111 (Figure 11a,b).
Similarly, the photothermal therapy performance by Au
nanoparticles varies depending on the particle size and
shape137,139 (Figure 11c,d).
Second, the nanoparticle size directs the EPR effect, and
thus, the optimum size requirement for the EPR effect is
required for tumor therapy via a passive targeting. For example,
nanoparticles of 50−100 nm size are used for prolonged blood
circulation and higher tumor accumulation141 (Figure 12).
Third, cellular therapy requires an optimum size in the range
of 5−50 nm, which is critical for cellular and subcellular
targeting. For example, active tumor therapy requires 5−10 nm
nanoparticles that have a greater cell penetration ability, which
is critical for an efficient drug delivery to the intracellular
compartment. Similarly, cell therapy by various nanoparticles
utilizes sizes in the range of 5−50 nm.17 Moreover, the surface
chemistry and chemical composition of nanoparticles are
intimately mixed with these size effects. For example, a tumor
accumulation of spherical gold nanoparticles of 15−100 nm
size depends on the surface chemistry, and transferrin-
conjugated nanoparticles have 5 times faster and twofold
higher tumor uptake than PEG-terminated gold nanoparticles
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Figure 12. Nanoparticle size effect in tumor therapy. (a) Schematic representation of the origin of a nanoparticle size effect in tumor targeting via
an EPR effect. Precisely, on the one hand, a nanoparticle with a 50−100 nm diameter exhibits a prolonged circulation time and a higher tumor
accumulation but poor tumor penetration. On the other hand, 5−10 nm nanoparticles have a greater tumor penetration ability, which is critical for
an efficient drug delivery. (b) Size effect of blood-clearance profile. (c) Size effect of nanodrug in antitumor activity. Adapted with permission from
ref 141. Copyright 2015 American Chemical Society.

of similar size. The reason is due to the active targeting of
transferrin-conjugated nanoparticles compared to passive
targeting by PEG-terminated nanoparticles.140 In another
example, trehalose-terminated and polymer-coated iron oxide
nanoparticles of 20−50 nm hydrodynamic size show a better
inhibition of polyglutamine aggregation in the mouse brain
than control nanoparticles without any trehalose conjugation
or polymer coating.14 The reason is that an appropriate coating
with a zwitterionic surface charge offers better brain targeting,
and conjugated trehalose offers an inhibition of polyglutamine
aggregation. Another example is the nanoparticle size effect in
inhibiting amyloid protein aggregation and minimizing the
cytotoxic effect that arises from these protein aggregates
(Figure 13). Because amyloid aggregation can occur in the
extracellular space or in the intracellular space, the nano-
particle-based strategy requires action either in the extracellular
space or at the intracellular location. One example is the
nanoparticle size effect in such a fibrillation process, where
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larger Au nanoparticles accelerate an Aβ fibrillation, whereas
smaller Au nanoparticles suppress this process. However,
polyglutamine aggregation, which occurs in the intracellular
space, requires relatively large Au nanoparticles (>20 nm),
because they must enter the cell via endocytosis.14,146
6. BIOMEDICAL APPLICATION OF SELECTED
NANOPARTICLES USING OPTIMUM SIZE
A library of functional nanomaterials has been synthesized and
used in a wide variety of biomedical applications.29 These
nanomaterials generate a large pool of experimental data that
offer an ideal particle size and functionalization toward
different biomedical applications. Table 4 summarizes some
of the selected examples of functional nanoparticles with
demonstrated biomedical applications and optimum
sizes.152−173 In addition, the role of size that has been utilized
for specific biomedical applications has been highlighted. In
summarizing these data, we can conclude that the particle size
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Figure 13. Effect of Au nanoparticle size in a fibrillation process. (a) Schematic representation showing that larger Au nanoparticles accelerate Aβ
fibrillation, whereas smaller Au nanoparticles suppress this process. (b) TEM images of Aβ(1−40) fibrils formed in the presence of Au
nanoparticles showing that smaller nanoparticles effectively suppress fibrillation. Adapted with permission from ref 146. Copyright 2017 Royal
Society of Chemistry.
effect has been exploited in four specific aspects. First, the high
surface curvature and high surface area of smaller nanoparticles
are utilized for the enhanced binding/adsorption of bio-
molecules. For example, a high surface curvature of 5 nm QDs
is used for a better binding of kinked DNA over straight
DNA.152 The higher surface area of anisotropic hydroxyapatite
nanoparticles is used for an enhanced number of sacrificial
bonds with collagen fibers in bone that offer a better
mechanical strength.38 Second, the size-dependent optical
properties of nanoparticles are used for an imaging/detection
of single biomolecules. For example, the bright plasmonic
property of larger Au/Ag nanoparticles is utilized for single-
molecule detection153,154 or single base-pair mismatch
detection in oligonucleotides,161 and the bright fluorescent
property of less than 5 nm QDs along with polymer shells is
used for the cellular uptake and tracking of single proteins
inside cells.157,159,162 Third, the optimum size is combined
with an appropriate surface chemistry for controlling cellular/
subcellular targeting and therapy. For example, the caveolae/
lipid raft uptake of nanoparticles followed by a subcellular
targeting is achieved via a controlled biofunctionalization of
20−30 nm particles,164−166 monovalent QDs of 10−15 nm
size are used for imaging receptors in living cells,160 and direct
membrane penetration followed by cytosolic delivery without
any vesicular entrapment is achieved via an arginine
conjugation of less than 10 nm particles.149 A similar size
effect has been used for various cell therapy applications. For
example, folate-functionalized iron oxide nanoparticles of 20−
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30 nm size are used for a vitamin C-based cell therapy via the
intracellular Fenton reaction,171 polymer micelles of 15−30
nm size are used for the clearance of toxic amyloid proteins via
cellular autophagy induction,170 and piezocatalytic BaTiO3
nanoparticles of 100−200 nm are used for an ultrasound-
based cell therapy.172 Fourth, the optimum size for the EPR
effect and less than 6 nm size requirement in renal clearance
are utilized for in vivo targeting/imaging/therapy applications.
For example, a rapid blood clearance of less than 6 nm particles
is used for a positron emission tomography (PET) imaging of
organs followed by a clearance from the body,163 functional
QDs of 10−20 nm size are used for imaging metastatic
cancer,156 cylindrical polymer micelles of less than 100 nm
diameter are used for better tumor targeting via longer blood
circulation,158 transferrin-conjugated nanoparticles of 20−30
nm size are used for crossing the blood-brain barrier,169 and
trehalose-conjugated iron oxide nanoparticles of 20−50 nm
size are used for inhibiting polyglutamine aggregation in mouse
brain.167 In particular, clinically approved nanoparticles and
nanodrugs are designed for delivery/imaging/therapeutic
applications based on size requirements and biocompatibil-
ity/biodegradibility.98,174 Specifically, lipid-based liposomal
structures or biopolymer-based nanomaterials of 50−150 nm
sizes are used as nanocarriers, and nontoxic iron oxide-based
nanoparticles of 50−100 nm are used for bioimaging
applications in various diseases, such as cancer, iron deficiency
disease, kidney disease, and multiple sclerosis.98,174
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Table 4. Selected Examples of Unique Biomedical Application using Nanoparticles of Optimum Size
nanoparticle used,
demonstrated biomedical application functionalization with optimum size used, key role of size refs
differentiating kinked and straight DNA QD, DNA 5 nm, high surface curvature 152
single-molecule detection Au/Ag, dye 50−100 nm, plasmonic property 153,154
bone with high mechanical strength hydroxyapatite, collagen fiber 10 nm, maximum sacrificial bonding between collagen 38
fibrils and nonfibrillar organic matrix
tracking single protein in living cell QD, streptavidin/antibody 5−10 nm, fluorescence property and endocytosis 157,159,162
imaging receptors in living cells QD, monovalent streptavidin 10−15 nm, optical property and endocytosis 160
detecting single base-pair mismatch in Au, oligonucleotide 12 nm, optical property 161
oligonucleotide
renal clearance after PET imaging CuS, polymer <6 nm, rapid blood clearance 163
caveolae-/lipid raft mediated cell uptake that bypass QD, folate/galactose/TAT 20−30 nm, cell uptake via modular interaction 164−166
endosomal/lysosomal trafficking peptide with <25 per QD
direct cell membrane translocation of nanoparticle Au, arginine <10 nm, temporary cell membrane opening 149
vitamin C-based cancer cell therapy iron oxide, folate 20−30 nm, high cell uptake 171
ultrasound-based cell therapy BaTiO3, FITC <100 nm, high cell uptake 172
clearing amyloid aggregates via cellular autophagy polymer micelle, arginine-amine 15−30 nm, cell uptake via lipid raft 170
induction
better tumor targeting carrier cylindrical polymer micelle, PEG <100 nm diameter with micron length, longer blood 158
circulation
imaging of metastatic cancer QD, dye and peptide 10−20 nm, in vivo targeting 156
multidrug delivery carrier biopolymer, drug 100−200 nm, in vivo targeting and cell delivery of drug 155
brain targeting via transcytosis Au, transferrin 20−30 nm, high cell uptake 169
inhibiting polyglutamine aggregation in brain iron oxide, trehalose 20−30 nm, in vivo targeting and high cell uptake 167
drug delivery via direct membrane penetration Au, arginine <50 nm, cell delivery via lipid raft 168
brain delivery using focused ultrasound Au, microbubble-based 15 nm, permeation through temporarily opened blood- 173
mechanical force brain barrier
clinic nanodrug liposome/polymer 50−150 nm, longer blood circulation 98,174

7. CONCLUSIONS
We have summarized the size effect of nanoparticles toward
various biomedical applications and highlighted the optimum
size requirements for the best performance. The most common
biomedical applications include drug delivery, fluorescent cell
imaging probes, protein detection/imaging, tumor targeting,
cellular and subcellular delivery of drugs, nanoparticle-based
cell therapy, and controlling cellular functions such as
endocytosis/apoptosis/autophagy. The designed nanoparticles
that are used for these applications vary from inorganic to
organic with their colloidal nature and size in the range of 2−
200 nm. A wide variety of functional nanoparticles have been
developed with demonstrated biological functions, and the
field is expected to grow further in the next decade.
Clearly, there is a correlation between the optimum size
requirement for various biomedical applications and the size of
various nanoscale units present in life processes, which are
selected via biological evolution. In both cases, the size range
appears to be broadly between 1 and 100 nm in most cases.
We propose that this size correlation is linked to the following
four aspects with respect to molecular or bulk materials
(Figure 14). First, nanosizes offer curved surfaces with high
surface-to-volume ratios, and the curvature can be controlled Figure 14. Four major roles of nanoscale units that are present in life
by varying the size.175−177 This circumstance can induce a processes and their importance in various biomedical applications.
tunable adsorption/binding of biomolecules with an enhanced
biological activity compared to flat surfaces or bulk materials. that can be controlled by changing the particle size. Examples
Examples include bone formation via the nucleation of include a receptor-mediated endocytosis of foreign materials,
hydroxyapatite, protein−protein interactions during enzymatic interactions of substrates with enzymes, sacrificial bond
reactions, and protein−DNA interactions during the repli- formation between inorganic and organic components of
cation and cellular uptake of foreign materials during bone, and interactions of cells with viruses. Third, the
endocytosis. Second, nanosizes offer multivalent binding with nanoparticle form of materials offers an easier option for the
biological interfaces compared to monovalent interactions with entry and transport of foreign material inside living bodies.14,29
molecules.165−167,178 This circumstance offers options for In particular, water-insoluble molecules/bulk material can be
modular and reversible interactions with biological interfaces prepared in water-dispersible and colloidal forms for better
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biological accessibility. Fourth, the utilization of unique
physical/chemical properties of selected materials requires
their nanoparticle form. Examples include the navigation of
bacteria using magnetic nanoparticles,42 liquid crystalline
ordering of anisotropic biological macromolecules and viruses
via entropy-driven self-assembly,94,179 and efficient sunlight-
harvesting properties of green plants via a nanoscale
assembly.46
Although many advancements have been made in under-
standing the size effect at the nanoscale and the size effects
have been successfully utilized in several biomedical
applications, there are many issues that remain to be solved.
Important issues in biomedical science include the design of
nanoscale materials for an effective transcytosis for brain
delivery,169 controlling intracellular processes (e.g., exocytosis,
transcytosis, autophagy induction),12,14,15 wireless cell/tumor
therapy via designed nanoparticles,173 nanodrugs with more
effective cellular/organ targeting,12,14−17 bioresponsive nano-
drugs with more effective therapy, designed nanoparticle-based
wireless therapy in remote regions,173 and nanoparticle-based
oral drug delivery.180 It is expected that the current
understanding of the field will offer the design of more
advanced functional nanomaterials for solving these issues.
Moreover, detection/imaging platforms with single-molecule
sensitivity will be improved further, which will further enhance
our understanding of the observed size effects.
■ AUTHOR INFORMATION
Corresponding Author
Nikhil R. Jana − School of Materials Science, Indian
Association for the Cultivation of Science, Kolkata 700 032,
India; orcid.org/0000-0002-4595-6917;
Email: camnrj@iacs.res.in
Authors
Jayanta Dolai − School of Materials Science, Indian
Association for the Cultivation of Science, Kolkata 700 032,
India; orcid.org/0000-0001-6800-2756
Kuheli Mandal − School of Materials Science, Indian
Association for the Cultivation of Science, Kolkata 700 032,
India; orcid.org/0000-0001-9705-5419
Complete contact information is available at:
https://pubs.acs.org/10.1021/acsanm.1c00987
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
N.R.J. acknowledges DST-SERB (CRG/2019/000030), Gov-
ernment of India, for financial assistance. J.D. acknowledges
CSIR, India, for providing a research fellowship.
■
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