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\DOI{10.5802/crchim.348}
\datereceived{2024-09-24}
\daterevised{2024-09-25}
\dateaccepted{2024-09-27}
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\CDRsetmeta{articletype}{review}

\title{Precision nanoparticles for drug delivery, cell therapy tracking, and theranostics}

\alttitle{Nanoparticules de pr\'{e}cision pour la d\'{e}livrance de m\'{e}dicaments, le suivi de th\'{e}rapies innovantes et le th\'{e}ranostic}

\author{\firstname{Delphine} \lastname{Felder-Flesch}\CDRorcid{0000-0003-3174-4072}}
\address{SUPERBRANCHE SAS Strasbourg, France}
\address{CNRS and Strasbourg University, Institute of Physics and Chemistry of Materials (IPCMS), UMR 7504 Strasbourg, France}
\email[D. Felder-Flesch]{Delphine.felder@superbranche.com}

\author{\firstname{Laura} \lastname{Talamini}\CDRorcid{0000-0001-6010-2947}}
\address{CNRS and Strasbourg University, Unit Biotechnology and Cell Signaling, UMR7242 Strasbourg, France}
\address{Strasbourg Drug Discovery and Development Institute (IMS), Strasbourg, France}
\email[L. Talamini]{talamini@unistra.fr}

\author{\firstname{Sylviane} \lastname{Muller}\CDRorcid{0000-0002-0481-0620}\IsCorresp}
\addressSameAs{3}{CNRS and Strasbourg University, Unit Biotechnology and Cell Signaling, UMR7242 Strasbourg, France}
\addressSameAs{4}{Strasbourg Drug Discovery and Development Institute (IMS), Strasbourg, France}
\address{University of Strasbourg Institute for Advanced Study (USIAS), Strasbourg, France}
\email[S. Muller]{sylviane.muller@unistra.fr}

\shortrunauthors

\keywords{\kwd{Multifunctional nanoparticles}
\kwd{Tissue targeting}
\kwd{Precision medicine}
\kwd{Cell therapies}
\kwd{Extracellular vesicles}
\kwd{Nanotheranostics}
\kwd{Cancer and inflammation}}

\altkeywords{\kwd{Nanoparticules multifonctionnelles}
\kwd{Ciblage de tissus}
\kwd{M\'{e}decine de pr\'{e}cision}
\kwd{Th\'{e}rapies cellulaires}
\kwd{V\'{e}sicules extracellulaires}
\kwd{Th\'{e}ranostique}
\kwd{Cancer et inflammation}}

\thanks{CNRS, University of Strasbourg Institute for Advanced Study
(USIAS), Interdisciplinary Thematic Institute IMS, as part of the ITI
2021-2028 program of UNISTRA, CNRS and Inserm (ANR-10-IDEX-0002), SFRI
(STRAT'US project, ANR-20-SFRI-0012), French National Agency for
research (ANR-21-CE17-0026), European Union's Regional Development Fund
in the context of the Interreg V Upper Rhine program, FHU ARRIMAGE,
OMAGE projects funded by Region Grand-Est and FEDER}

\begin{abstract}
For more than two decades, nanoparticles have attracted a great deal of
attention from researchers and developers. {When properly designed,
vectorized nanoparticles represent high-value-added tools with
potentially invaluable properties in a number of areas, including
biology, biotechnology, and medicine owing to their exceptional
physico-chemical properties, especially resulting from their high
surface area,} {high loading capacity, and nanoscale size. Smart design
and building of nanoparticles through appropriate surface chemistry and
functionalization provide a material that possesses multifunctional
capabilities, able to specifically interact with a selected target,
release a compound in a controlled and sustained way, and overcome, if
desired, biological barriers} {such as the blood--brain barrier or lung
barriers of interest. Unique constructions have thus opened up original
and innovative possibilities in biotechnological and biomedical fields
such as imaging, biosensors, rapid diagnostics, drug delivery, medical
implants, and tissue engineering. This article briefly describes the
main types of nanoparticles that have been developed and their advantages
and disadvantages depending on the intended application, and highlights
some remarkable results achieved recently in the biomedical field.
Certain dangers or fears regarding their use in human and animal
therapy or for users have been mentioned. Finally, conclusions and
future perspectives are provided.}\looseness=-1
\vspace*{-2pt}
\end{abstract}

\begin{altabstract}
Depuis plus de vingt ans, les nanoparticules attirent beaucoup
l'attention des chercheurs et d\'{e}veloppeurs. Bien con\c{c}ues, les
nanoparticules vectoris\'{e}es repr\'{e}sentent des outils de haute
valeur ajout\'{e}e poss\'{e}dant des propri\'{e}t\'{e}s potentiellement
inestimables dans de nombreux domaines, comme notamment la biologie, la
biotechnologie et la m\'{e}decine, ceci en raison de leurs
propri\'{e}t\'{e}s physico-chimiques exceptionnelles, r\'{e}sultant en
particulier de leur surface \'{e}lev\'{e}e, de leur grande capacit\'{e}
de chargement et de leur taille nanom\'{e}trique. La conception et la
fabrication intelligentes de nanoparticules par le biais d'une chimie
de surface et d'une fonctionnalisation appropri\'{e}es fournissent des
nano-objets qui poss\`{e}dent des capacit\'{e}s multifonctionnelles,
capables d'interagir sp\'{e}cifiquement avec une cible
s\'{e}lectionn\'{e}e, de lib\'{e}rer un compos\'{e} de mani\`{e}re
contr\^{o}l\'{e}e et durable et de franchir, lorsque cela est
souhait\'{e}, des barri\`{e}res biologiques, telles que la barri\`{e}re
h\'{e}mato-enc\'{e}phalique ou des barri\`{e}res pulmonaires
d'int\'{e}r\^{e}t. L'obtention de ces constructions uniques a ainsi
ouvert des possibilit\'{e}s originales et innovantes dans divers
domaines de la biotechnologie et de la biom\'{e}decine tels que
l'imagerie, les biocapteurs, le diagnostic rapide, l'administration de
m\'{e}dicaments, les implants m\'{e}dicaux et l'ing\'{e}nierie
tissulaire. Cet article d\'{e}crit bri\`{e}vement les principaux types
de nanoparticules qui ont \'{e}t\'{e} d\'{e}velopp\'{e}s, leurs
int\'{e}r\^{e}ts et inconv\'{e}nients selon l'application que l'on
projette, et met en valeur des r\'{e}sultats remarquables acquis
r\'{e}cemment dans les domaines biom\'{e}dicaux. Certains dangers ou
craintes vis-\`{a}-vis de leur utilisation en th\'{e}rapie humaine et
animale ou pour les utilisateurs sont \'{e}voqu\'{e}s. Enfin, des
conclusions et des perspectives d'avenir sont pr\'{e}sent\'{e}es.
\end{altabstract}

\maketitle

\twocolumngrid

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{
\section{Introduction} 

Delivering small molecule or peptide drugs, biologics, or any viable
cells in a safe, painless, targeted, efficient, and cost-effective way
remains a central concern for all researchers and developers of future
medicines. However effective an active compound may be, if it is not
properly administered, and/or\break delivered to the right site and at the
right time, with the right dose, all its effectiveness may be lost.
This explains why there is a long way to go between tests carried out
ex vivo on cells, in~vivo with laboratory animals and
finally in human beings with their own heterogeneity and complexity.
Another challenge that has to be met is to resist stomach acid and
pass biological barriers (skin, pericardium,\break blood--brain barrier
[BBB], mucous membranes, tears, earwax, mucus) that are heterogeneous
across patients and can be impaired in diseases. It should be noted
that for certain applications, the passage of natural barriers, for
example to the brain, is not at all desirable.

{In recent years the quest to refine systems allowing the targeted
delivery of drugs has exploded and led to extraordinary developments,
especially by using ``intelligent'' nanoparticles (NPs) for applications
in nanomedicine, therapy, and diagnostics}~\cite{1,2,3,4,5,6,7,8,9}{.
NPs present a large spectrum of advantageous properties for biological
and medical applications. They can be designed to have specific surface
properties that allow them to selectively target abnormal cells, for
example, tumor cells}~\cite{10}, {while ignoring healthy ones, thereby
reducing deleterious effects of otherwise efficient drugs. NPs can be
engineered to liberate their cargo in a controlled manner, slowly or
rapidly, enabling the drug to be released at the right time, at the
intended site, for example, an inflammatory site, a tumor, or an
infected tissue. NPs also have decisive applications for diagnostic
purposes, as contrast agents (CAs) or tracers in medical imaging or, for
example, as detection probes of specific biomolecules in biological
samples}~\cite{3,6}. {Finally, they can be internalized in cells to
ensure hyperthermia-mediated treatment of cancer}~\cite{11}.

{If it is largely recognized that in general NPs allow to improve drug
targeting, reduce side effects, and diminish potential toxicity
concerns of certain drugs, we cannot ignore that ethical considerations
related to safety access and affordability surround the use of
NP-based drug delivery systems}~\cite{12,13,14}. {We need to take
account of the fear felt by some patients, their families, and certain
opinion groups. In this review, we present the progress in NP designs
applied in both general and precision therapeutic applications in
tracking analyses and theranostics. We highlight the progresses that
have been made in recent years and some limitations that represent the
future challenges to pass in the next years. This field of research and
development is eminently cross-disciplinary. Constant progresses in all
areas (chemistry, material science, biophysics, pharmacology, cell
biology, cellular immunology, biomedical sciences) must merge to
innovate and produce increasingly effective and safe nanotools.} 
}

\section{Nanoparticles: Which one for diagnostics, tracking analysis,
and for therapy?}

{The ability to finely shrink materials to nanoscale dimensions from 1
to 100 nm has led to the production of NPs that exhibit unique
structural, chemical, and biological properties, paving the way for a
new field of research}~\cite{15}. {Understanding the influence of NP
properties on clinical translation issues such as pharmacokinetics,
pharmacodynamics, bioaccumulation, excretion mode, and toxicology is of
utmost importance}~\cite{16}. {These parameters classically assembled
under the general term ``critical nanoscale design parameters'' include
their size, shape, surface functions, rigidity or flexibility,
architecture (their design), and elemental composition 
influencing their biodegradation, biodistribution as well as
their immune recognition.} 


{Over the past two decades, the development of functional NPs
has progressed exponentially into a broad range of applications in
biology, technology, and medicine. As mentioned above, successful
applications especially include targeted therapy, and their use as
molecular probes, aiding in cell tracking and imaging
diagnostics}~\cite{17} {(Figure~\ref{fig1}).}

\begin{figure*}
\includegraphics{fig01}
\caption{\label{fig1}Application of nanoparticles. Photodynamic therapy
(PDT), magnetic resonance imaging (MRI), magnetic particle imaging
(MPI), and computed tomography (CT).}
\vspace*{2em}
\end{figure*}

{Labeling cells, such as stem cells, with NPs enables tracking their
path in the body and identifying cell interactions}~\cite{18}.
{Furthermore, NPs can be used as CAs or tracers to improve
the imaging of internal organs, for instance, aiding in the early
detection of tumors}~\cite{19} {or specific area of gut
inflammation}~\cite{20}. {The application of NPs in cell targeting
exploits several of their unique features, namely their small size, the
high surface-to-volume ratio, and their chemical
functionalities}~\cite{21}. {Numerous articles have been published
describing these aspects, guiding us toward the choice of the right
matter for the right purpose}~\cite{22}. {According to a recent
survey}~\cite{23}, {the most commonly used NPs for cell tracking and
diagnostic purposes are inorganic NPs, accounting for 79\% of the total
work relating the remarkable properties of NPs. In this class of
material, the most common are iron oxide and gold NPs (Figure~\ref{fig2}).}

\begin{figure*}
\includegraphics{fig02}
\caption{\label{fig2}Schematic illustration of different classes of NPs. 
Based on the material composition, NPs are classified into hard and soft
NPs. Hard NPs include gold NPs, iron oxide NPs, and  silica and
mesoporous silica NPs. Soft NPs include lipid-based NPs,
polymeric NPs, and dendrimers.}
\end{figure*}

\subsection{Iron oxide NPs}

{The first example of potential inorganic NP candidates are iron
oxide NPs (IONPs), which are mainly composed of magnetite
(Fe}$_{3}${O}$_{4}${), maghemite
(${\rmgamma}$-Fe}$_{2}${O}$_{3}${), and mixed
ferrites}~\cite{24}. {IONPs combine magnetic properties and low
toxicity, providing the advantage of delivering high-resolution images
of human soft tissue} {{via}} {magnetic resonance imaging (MRI)
in a safe way}~\cite{25,26}. {Therefore, IONPs have already been
exploited commercially as T2 (see footnote\footnote{There are two types of relaxation
time: T1, longitudinal relaxation time (in the order of a second) and
T2, transverse relaxation time (expressed in milliseconds). In MRI, T1
signal is characterized by the time it takes for hydrogen atoms to
return to 63\% of their equilibrium position at the end of a pulse.})
CAs for MRI}~\cite{27}, {and are of particular interest as
biodegradable nanoobjects compared to other CA
families}~\cite{28}. {They can also be used as magnetic particle
imaging (MPI) tracers}~\cite{29} { or as a magnetic particle hyperthermia
tool to treat cancer by heating solid tumors to 41--47~\textdegree C
for a defined time to achieve a prescribed thermal dose}~\cite{30}. {To
date, a type of amino silane-coated superparamagnetic IONP (SPIONs),
called Nanotherm was the only formulation approved in magnetic
hyperthermia for the treatment of primary or recurrent glioblastoma
multiform and is now in clinical trials to treat prostate
cancer}~\cite{31}.

{Combining imaging and therapeutic properties, IONPs are thus prime
candidates for a theranostic approach to nanomedicine}~\cite{32}.
{Ultrasmall} {\mbox{SPIONs} (USPIOs) (${<}$5 nm) showed reduced
longitudinal and transverse relaxation times, offering a better T1
contrast (brighter images; see footnote 1) where they accumulate,
comparable to the common gadolinium-based CAs}~\cite{24,33}. {Moreover,
negatively charged USPIOs also showed a tropism to activated
macrophages in highly inflamed areas avoiding off-target
accumulation, suggesting their safer use in targeting imaging of
inflammatory disease states}~\cite{33}. {Functionalization of IONPs has
resulted in efficient cellular uptake and reduced toxicity}~\cite{34}{;
indeed, to improve their internalization in cells lacking in phagocytic
capacity as mesenchymal stem cells, different positive coatings were
used such as poly-L-lysine, chitosan, 2-aminoethyl-trimethyl \mbox{ammonium,}
amphiphile lipopeptide, and poly(lactic-co-glycolic) acid
(PLGA)}~\cite{35}. {In terms of active targeting to boost NP uptake in
cancer cells, IONPs have been functionalized with moieties such as
transferrin and its analogues, antibodies (e.g., targeting epidermal
growth factor receptor [EGFR], endothelial growth factor, herceptin, or
CD44, involved in cell--cell interactions, cell adhesion and
migration), aptamers (single-stranded nucleic acid ligands
or peptides that bind to target molecules with high affinity and
specificity), hyaluronic acid, folates, glucose, and peptides including
chlorotoxin, Arg-Gly-Asp peptide (RGD), and Glu-Pro-Pro-Thr peptide}~\cite{36}.

\subsection{Gold NPs}

{Among metals, gold is emerging as a promising material for imaging,
diagnosis, and cell tracking. Gold NPs are biologically inert,
biocompatible, easily tailored with functional groups, and their size
and shape are highly tunable}~\cite{37,38}. In vivo
{studies confirmed that gold NPs can passively accumulate in tumor or
inflamed sites through enhanced permeability and retention
effect}~\cite{39}.

{With the advancement of new therapies as cell-based therapy, there is
an increasingly urgent need for methods capable of monitoring the injected
cells to determine their fate and functions. Computed tomography (CT)
is a non-invasive imaging technique widely used in clinics that provides
three-dimensional anatomical information of specific organs and improves
diagnoses and treatment efficacy. One of the limits of CT is its lower
sensitivity toward CAs}~\cite{40,41}. {As a consequence, the large
doses of} {iodine-based} {CAs needed} {can cause allergy reactions and
kidney toxicity in patients}~\cite{42}. {Some of these limitations have
been overcome using newly emerging gold NPs-based CAs}~\cite{43,44}. 
{Various gold NPs have been investigated for CT
imaging applications in tumors, thrombi, kidneys, and bones. Due to
their high flexibility in coating and targeting, ligand-decorated gold
NPs exhibit enhanced tissue-specific molecular reactivity compared to
iodine or other nanomaterials. Notable examples include gold 
NPs conjugated to anti-integrin} {RGD tripeptides, anti-EGFR-2 as well as
peptides such as the prostate-specific membrane antigen, RNA aptamers,
and folic acid, all of which demonstrate improved accumulation in
tumor cells}~\cite{39}. {\mbox{Successful} examples of immune cell tracking
(e.g., dendritic cells and T-cells) include the use of gold NPs
coated with glucose molecules and conjugated to anti-Programmed
Death-Ligand 1 (PD-L1) antibodies, thiolated adenine-rich
oligonucleotides, and poly(amidoamine) dendrimers}~\cite{45,46,47,48}.
{Similar to IONPs, it is important to note that other physico-chemical
properties such as size and shape significantly influence cellular
uptake and their biodistribution. Gold NPs smaller than 6 nm are
rapidly excreted by the kidneys}~\cite{49} {while ${\sim}$13
nm gold NPs show slower tissue penetration but increased accumulation
over time, compared to larger, ${\sim}$50 nm gold NPs.
Moreover, gold NPs exhibit shape-dependent bioaccumulation; for
example, star-shaped gold NPs were shown to display similar kinetics to
spherical gold NPs in the liver and spleen but a distinct tropism to
the lungs}~\cite{50}.

{NP systems represent also a successful tool for drug delivery.
Although some hard NPs, such as mesoporous silica, are used for this
purpose}~\cite{51}, {most of the strategies are based on soft materials
such as lipid NPs and polymeric NPs}~\cite{52,53}. {These NPs present
an empty cavity where the therapeutic molecule is hosted and protected
from degradation.} 

\subsection{Lipid NPs}

{Lipid  nanoparticles (LNPs; Figure~\ref{fig2}) have gained broad use in
medical research. Since Doxil}{$^{\text{\textregistered}}$}, {the first liposome
doxorubicin nanodrug, was approved for the treatment of different types
of cancers, several nanoformulations (DaunoXome, AmBisome, Myocet, and
DepoCyt) have been released on the market, especially in the context of
cancer immunotherapy}~\cite{52}. {In addition to their application in
oncology, LNPs have recently been approved for the delivery of mRNA and
small interfering RNA (siRNA) in coronavirus disease (COVID)-19
vaccines and amyloidosis treatment, respectively}~\cite{54}. {Recently,
Ferraresso et~al.\ tested clinically approved LNP formulations, in a
swine model, carrying mRNA to demonstrate the expression of exogenous
mRNA and protein synthesis in non-reticulo-endothelial system organs
without eliciting over toxicity}~\cite{55}.

{LNPs are based on lipid molecules such as natural or synthetic
phospholipids, which form the backbone of spherical vesicles, cationic
or ionizable lipids, which allow the attachment of \mbox{negatively} charged
molecules such as nucleic acid and PEGylated lipids that increase the
``stealth'' property, thus increasing stability and circulation time in
biological fluids. Due to their nature and biomimetic architecture,
LNPs are considered highly biocompatible and the least toxic
NPs}~\cite{56}. {LNPs are highly versatile drug delivery systems that
can encapsulate different types of therapeutic agents. This exceptional
property is linked to their unique structure: hydrophilic drugs in
their core, hydrophobic drugs within the phospholipid bilayers, and
amphiphilic drugs in both regions}~\cite{57}. {As for the other NPs,
their size, charge, and capacity to accept surface modifications can
influence their biodistribution in a decisive manner. Extensive
literature has documented how physico-chemical properties can influence
cellular uptake and tropism to areas of inflammation. For example,
small NPs (${<}$100 nm) have high rates of cell internalization
and extended circulation time while in contrast, larger NPs that show a
lower cell uptake can offer higher drug loading capacity. A high
surface charge (negative or positive) has been demonstrated to reduce
particle aggregation favoring the monodisperse and stable
system}~\cite{38,58}. {Furthermore,  surface antibody
conjugation}~\cite{59}, {cell-specific moieties such as
E-selectin/CD62E}~\cite{60}, {a cell adhesion molecule expressed on
endothelial cells, or aptamers}~\cite{61} {represent a good strategy
to improve the targeting. In this sense, Kim et~al.\ used 
dual-aptamer-conjugated liposomes to target mucin 1 and CD44 antigen 
(a~cell-surface glycoprotein involved in cell--cell interactions, cell
adhesion and migration, especially of tumor cells) present on both
breast cancer and cancer stem cells, respectively}~\cite{62}. {The
functionalization and the shield offered by LNPs promote both the
selective targeting and drug integrity. This strategy was used to
encapsulate immunomodulatory drugs such as Janus kinases and nuclear
factor-kappa B inhibitors, viral and self-antigens, and microRNA
(miRNA) and siRNA}~\cite{38,63}. {Similarly, Paoletti et~al.\ found an
efficient way to deliver small RNA to monocytes and macrophages
reducing joint inflammation in the mouse model of rheumatoid arthritis.
AntagomiR-155-5p encapsulated in PEGylated LNPs presented the advantage
to selectively target and correct the defect of polarization of
monocytes into anti-inflammatory macrophages}~\cite{64}. {Controlling
the drug release is another challenge that has been achieved with LNPs
by engineering their backbone to be sensitive to diverse stimuli, such
as redox environment, presence of specific enzyme, and change in pH or
hypoxia (i.e., when levels of oxygen are low in  body
tissues)}~\cite{65}. 

\subsection{Polymeric NPs} 

{Due to their remarkable versatility, polymers, both natural and
synthetic, have been extensively utilized in the development of
nanometric colloidal systems (Figure~\ref{fig2}). These systems offer numerous
benefits, including biodegradability, biocompatibility, and low
toxicity}~\cite{4}. {Encapsulating therapeutic molecules within
polymeric NPs has been demonstrated to enhance drug bioavailability,
extend the release profile, safeguard the cargo from enzymatic
degradation, and minimize cytotoxicity}~\cite{66}.

{The use of biodegradable polymers or labile cross-linkers represents an
interesting approach for making degradable polymeric carriers. For
example, extensive studies have been conducted using natural polymers such
as chitosan, alginate, gelatin, and albumin}~\cite{53}. {A
groundbreaking development in the formulation of paclitaxel (PTX) was
marked by the market approval of Abraxane, an albumin NP formulation
loaded with PTX. Clinical data clearly demonstrated the superiority of
this NP-based approach, particularly in reducing PTX toxicity, which
allowed for a higher maximum tolerated dose in cancer
patients}~\cite{67}. {Several other polymers with biodegradable
properties have been largely described in the literature, including
PLGA, poly(${\rmvarepsilon}$-caprolactone), and many others}~\cite{68,69}.
{Such polymers were applied to promote the gradual release of cargo
(e.g., immunosuppressant agents), fostering the reduction of
inflammatory signals in autoimmune and acute inflammatory
diseases}~\cite{70}.

{Polymeric NPs can encapsulate different types of cargo including
hydrophilic and hydrophobic drugs, proteins, and nucleic acids. As
described for other NPs, surface-bound targeting ligands can enhance
the delivery of drugs to specific sites and bind pro-inflammatory
cells. For instance, PLGA NPs were designed to attach to tumor
necrosis factor receptor 1 on macrophages and intercellular adhesion
molecule~1 on endothelial cells at the site of disease}~\cite{70}.
{Zhang et~al.\ described experimental results showing that
galactosylated chitosan NPs achieved significantly higher uptake by
intestinal activated macrophages in a mouse model of inflammatory bowel
disease}~\cite{71}.

{Dendrimers are an important group of nanostructured polymeric carriers
for the development of nanomedicine to treat various
diseases}~\cite{72}.\break Because of structural diversity and adaptability,
they have been used to deliver drugs and genes in many ways. For
instance, dendrimers with a hydrophobic core and a hydrophilic
periphery may behave like unimolecular micelles, and they have been
utilized to solubilize hydrophobic drugs by entrapping them in the
intramolecular cavity~\cite{73}. Cationic dendrimers have been
extensively applied as non-viral gene carriers~\cite{74}. Dendrimer
surface groups can be conjugated with drugs and other functional\break
moieties~\cite{75}.

\subsection{Mesoporous silica NPs}

{Among hard NPs that show promises for drug delivery, mesoporous silica
NPs (Figure~\ref{fig2}) deserve particular attention. They can be synthesized to
give rise to NPs of different sizes, shapes, and levels of porosity.
Their porous structure allows for effective drug loading and provide
drug protection, while the outer surface can be further functionalized
with polymer, dyes, and targeting molecules}~\cite{76}. {Notably, silica
was defined as ``Generally Recognized as Safe'' by the Food and
Drug Administration (FDA), and several clinical trials are currently
underway utilizing silica-based NPs}~\cite{51}. {An example of such a
class of NPs is ultrasmall silica NPs (6--10 nm in size) called Cornell
dots, which are under evaluation in clinical trials (ClinicalTrials.gov
identifier/NCT number NCT03465618, NCT01266096, and NCT02106598). Their
small size allows clearance by the kidney. They demonstrated good
uptake by sentinel lymph nodes in patients with head or neck melanoma
to allow visualization during biopsy. In another study, the
functionalization with tumor-homing arginyl-glycyl-aspartic
acid-tyrosine (RGDY) 4-mer peptide and fluorescent dye Cy5.5 showed 
good uptake by tumor cells and an improvement by} {20 to 30 times for
the diagnosis and staging of melanoma and malignant brain
cancer}~\cite{51}.

\begin{figure*}
\vspace*{-2pt}
\includegraphics{fig03}
\vspace*{-2pt}
\caption{\label{fig3}Schematic illustration of OSCs administered in
tumor-bearing mice and their ability to escape from macrophage uptake
and exclusively target LSEC. Images depicted in green are lymphatic
endothelial cells, in red are NPs,  and in gray are nuclei (adapted
from~\cite{93}).}
\vspace*{-2pt}
\end{figure*}

{In parallel to mesoporous silica NPs, extensive investigations have
been focused on mesoporous organosilica NPs (Figure~\ref{fig2}). The presence of
organic moieties (disulfide, amide, oxamide, imine groups) in
inorganic silica lends itself to the characteristic of breakability under
precise environmental conditions controlling the release of the cargo
while retaining the features of silica NPs}~\cite{77,78,79}. {In this
context, we developed a valuable ``Trojan horse'' system based on
breakable silica-cage-like NPs (OrganoSilica nanoCages [OSCs]) able to
avoid macrophage uptake and specifically targeting liver sinusoidal
endothelial cells (LSECs). This nanotool holds the possibility for LSEC
modulation, impacting cellular and immunological processes such as tumor
cell extravasation, hepatic immunity, and tolerogenic state of immune
cells in autoimmune diseases}~\cite{80}\break {(Figure~\ref{fig3}).}

Altogether these data illustrate that according to the final purpose of
the project (therapy, diagnostics, tracking, or targeting), the type of
in~vitro or in~vivo models that are exploited, the
localized or systemic receptors that are targeted, and the dynamics of
the process that is required, a variety of nanomaterials are available
that can give excellent results if selected properly. The choice of
tools designed to follow the NPs, once they are administered into
experimental animals, is also multiple (Figure~\ref{fig1}). However, some
technical limitations remain to solve for certain applications such as
transdermal drug delivery or for magnetothermal brain stimulation to
mention just two examples, leading to intensify research further to
fill these gaps. 

\section{Magnetic nanoparticles for in~vivo cell and extracellular
vesicle therapy tracking}

Advanced therapy medicinal products (ATMPs) will be tomorrow what
transfusion is today: personalized\break medicine, based on expert knowledge
of cells or\break extracellular vesicles (EVs) to reverse disease. For
example, regenerative medicine, based on the transplantation of cells
produced in laboratories, is no longer the distant dream of a few
researchers, but a clinical reality that is being applied in numerous
therapeutic trials (\url{https://clinicaltrials.gov}). The time has therefore
come to anticipate the deployment of this new medicine to all patients,
whether affected by neurodegenerative pathologies, autoimmune diseases,
or cancer.

There is growing interest in cells and EV labeling using exogenous
markers such as NPs to identify and monitor in real time 
in~vivo {migration of transplanted therapies. Indeed, one of
the issues encountered in the field of ATMPs is the lack of information
on the biodistribution of cells and/or EVs once injected into the
patient. Therefore, non-invasive imaging methods such as MRI, for
example, should enable to better understand the functions of implanted
cells}~\cite{81}, {assess the efficacy of cell therapies}~\cite{82},
{and determine which therapeutic protocols give the highest probability
of regeneration or healing. Moreover, ensuring disruptive monitoring of
ATMPs} in~vivo {through MPI would not only enable
quantification}~\cite{83} {for possible dose reduction but also
mitigate the risk of cell therapy escape, with the possibility of
destroying injected cells in the event of uncontrolled multiplication}
{{via}} {the use of theranostic NPs and focalized magnetic
hyperthermia}~\cite{84}.


{Various techniques can be used to track ATMPs.} In vitro,
{the most widespread approaches are the use of bromodeoxyuridine or
green fluorescent protein}~\cite{85} {for the tracking of implanted
cells on histological examinations.} In vivo, {two types of
tracking are possible, either direct imaging or indirect tracking. In
the case of indirect monitoring, this involves using a reporter gene (an
exogenous coding region joined to a regulatory sequence of another gene
of interest)}~\cite{86}. {In the case of a direct follow-up, the tag
is internalized before the cells are injected. Several imaging
modalities are then possible, namely non-invasive MRI}~\cite{87}
{{via}} {the internalization of SPIONs
(}$^{1}${H-MRI) or perfluorocarbon derivatives
(}$^{19}${F-MRI)}~\cite{88}. {The latter option enables}
in~vivo {quantification and thus to join MPI or nuclear
imaging, such as positron emission tomography}~\cite{89}, {and single
photon emission computed tomography}~\cite{90}. {Immune cells and bone
marrow (BM)-derived stem cells were initially labeled with an}
$^{111}$In-oxine {radiotracer to determine their biodistribution in
patients using ${\rmgamma}$-camera imaging}~\cite{91}. {For the first
time, it was thus possible to visualize cells in the whole body without
the need of biopsies. However, radiotracers can exhibit significant
cytotoxicity and lack an infinite half-life. Furthermore, nuclear
imaging techniques do not provide anatomical information and high
spatial soft tissue contrast. This led to the development of
alternative non-invasive} in~vivo {cell tracking approaches
with MRI historically being one of the primary clinical imaging
modalities}~{\cite{66}, followed by MPI as a more recent preclinical
cell tracking\break technique}~\cite{92}.

{Focusing on magnetic tracers, if properly used, SPIONs do not alter
viability, function, proliferation, or differentiation of
cells}~\cite{93}. {However, an issue is possible as the tag may be
transferred to local, bystander cells such as tissue
macrophages}~\cite{94}, {especially in the areas of inflammation, thus
leading to confounding the microscopy or imaging interpretations. This
is of particular importance in direct implantation of cells into target
tissues, which can result in 50\% to 80\% cells undergoing cell
death}~\cite{95}. {\mbox{However,} a few studies showed that transfer of iron
to activated macrophages accounted for less than 10\% of the total iron
in labeled cells}~\cite{96}.

\subsection{Tracking cells with SPIONs}

{In 2018, H. Daldrup-Link and co-workers published a proof-of-concept
study in patients on the tracking\break of autologous BM-derived cell
transplants in femoral osteonecrosis with MRI}~\cite{97}. {This kind
of clinical imaging test is important as it may help to recognize
inter-individual differences in the delivered quantity and location of
transplanted cells, and correlate results with tissue repair outcomes.
It could become a powerful new tool to monitor the delivery and
engraftment of BM-derived therapeutic cells non-invasively in cancer
patients with the ability to directly impact patient management. The
same year, another group used a clinically applicable approach
combining the FDA-approved drugs heparin, protamine, and ferumoxytol (a
USPIO) to form nanocomplexes for magnetic
Natural Killer (NK) cell labeling so that NK cell biodistribution
could be visualized} in~vivo {with MRI following
transcatheter intrahepatic arterial (IHA) local delivery}~\cite{98}.
{The purpose of these studies was to test several hypotheses in a rat
model of hepatocellular carcinoma, and to determine if (1)
clinically applicable labeled NK cells can be tracked with MRI, (2)
transcatheter IHA NK infusion can improve NK cell homing efficacy to
targeted tumors, and (3) serial MRI monitoring of NK cell migration to
targeted tumors can serve as an early biomarker for prediction of
longitudinal\break response.}

{More recently, H. Daldrup-Link and colleagues successfully labeled
Chimeric Antigen Receptor (CAR) T-cells with ferumoxytol, thereby
paving the way for monitoring CAR T-cells in solid tumors}~\cite{99}.
{This work demonstrated the feasibility of approaches using
mechanoporation} {{via}} {a microfluidic chamber to label 
CAR T-cells with IONPs reaching a substantial labeling efficiency. It was
then possible to detect the transferred T-cells using several imaging
modalities, for example, MRI, photoacoustic imaging, and MPI. Such imaging
approaches, which allow monitoring the localization of the ATMP in a
dose-dependent manner, may contribute to elucidating the factors that
give rise to responders and non-responders of T-cell therapy against
solid tumors.} 

\subsection{Extracellular vesicle tracking}

{Human stem-cell-derived EVs are currently being investigated for
cell-free therapy in regenerative medicine applications, but the lack
of non-invasive imaging methods to track EV homing and uptake in
injured tissues has limited the optimization of the approach. In 2021,
G. Liu and co-workers, at Johns Hopkins University, developed an
electroporation labeling strategy to prepare magnetic EVs allowing MRI
tracking of systemically injected therapeutic EVs. Relying on the use
of ``sticky'' SPIONs coated with a poly-histidine tag, this new
labeling strategy allowed to efficiently separate magnetic EVs from
unencapsulated SPIONs particles. Using this method, MRI tracking of the
homing of systemically administered pluripotent stem cell
(iPSC)-derived magneto-EVs in different animal models of kidney injury
and myocardial ischemia was possible and showed that iPSC-derived EVs
preferentially accumulate in injury sites and confer substantial
protection}~\cite{100}.

{In summary, perspectives in the monitoring of ATMPs lie in combined
approaches such as MRI/MPI or MRI/}$^{19}${F-MRI/MPI for an efficient
quantification without the use of radiation}~\cite{101}, which {has proven
efficient for tracking adoptive T-cell immunotherapy}~\cite{102} {or
for monitoring the delivery of mesenchymal stem cells and the ensuing
inflammation}~\cite{103}. {Indeed, quantitatively monitoring
mesenchymal stem cell engraftment and ensuing inflammation over time
would be invaluable for evaluating the course of therapy.} 

\section{Nanoparticles and immunotherapy}

{Immunotherapy treatments include monoclonal antibodies, checkpoint
inhibitors, cytokines, vaccines, and CAR T-cell therapy. Often used in
the context of cancer, immunotherapy approaches are also used in the
case of infection and immune diseases, including autoimmunity. In
cancer, adoptive cellular therapy increases the number or the
effectiveness of immune cells, usually T-cell engagers, which improves the
power of the immune response against tumor cells}~\cite{104}. {Immune
checkpoint inhibitors, for example, ipilimumab (Yervoy$^{\text{\textregistered}}$)
that blocks cytotoxic T-lymphocyte antigen 4 (CTLA-4), pembrolizumab
(Keytruda$^{\text{\textregistered}}$) and nivolumab (Opdivo$^{\text{\textregistered}}$)
that target PD-1, and atezolizumab (Tecentriq$^{\text{\textregistered}}$) that
blocks PD-L1, prevent checkpoint proteins from binding with their
partner proteins. This precludes the ``off'' signal from being sent,
allowing T-cells to kill cancer cells. Cytokine-based immunotherapy
drugs target cytokine activity to the tumor microenvironment or to the
desired effector immune cells}~\cite{105,106}.

{Potentiating the effects of these biological and chemical tools is
central not only for increasing their local efficacy but also, as
introduced above in this\break review, for protecting the active compounds from\break
partial or full degradation on the way to their destination and to send
them to the right target. The challenge is huge because most tumors
with poor prognoses are not always locatable or accessible. Conversely,
in the case of immune system disorders, especially in systemic
autoimmunity, abnormal infiltrating immune cells are spread throughout
various organs. The percentage of T- or B-cells with precise antigenic
specificity is however extremely low. In these examples in cancer and
autoimmunity, therefore, a local therapy may be ineffective unless a
key organ or tissue is identified or a cell subgroup is shown to be
central to the regulation of other cell subtypes (as it is the case in
the abscopal effect}\break \cite{107,108}).


{It is beyond the goal of this short review to extensively describe the
many successful examples and also the failed preclinical studies that
have exploited NPs in immunotherapy protocols. Comprehensive reviews
have been recently published on this topic}~\cite{6,8,104,109}, {and
today a growing number of NPs have been approved by the FDA for
applications in nanomedicine}~\cite{4}. {Below, we selected a few
examples in which remarkable results were obtained these last few years.} 


{Schudel et~al.\ employed a two-stage delivery strategy to enhance the
uptake of NPs by cells within lymph nodes, which are typically
difficult to target\break with conventional drugs. In this approach, CpG\break
oligonucleotides were conjugated to 30 nm poly\break(propylene sulfide) NPs
using a degradable linker. This strategy resulted in increased uptake
by dendritic cells, T-cells, and cancer cells within the lymph nodes.
Additionally, by modulating the fragmentation half-lives of the linker,
the researchers were able to control the timing of the antigen release,
improving the precision and effectiveness of the delivery}~\cite{110}.
{T-cells are another key cell type to target. Polymer NPs coated with
DC membrane and conjugated with anti-CD3 antibodies \mbox{demonstrated}
\mbox{efficient} accumulation in draining lymph nodes. These NPs
effectively activated and expanded CD8}$^{+}$ {T-cells
and, when combined with anti-PD1 therapy, successfully elicited
anti-tumor immunity}~\cite{111}.


{Recently, Tamming et~al.\ formulated an LNP-based DNA vaccine encoding
the Delta spike protein of severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2). The administration of this nanosystem
enhanced the antibody response, providing strong protection against
subsequent\break infections. The vaccine reduced viral replication, prevented
lung tissue damage, and downregulated inflammatory pathways,
highlighting the potential of this nanosystem for broad protection
against various variants}~\cite{112}.


{In another field, LNPs were used recently in a research context on
pancreatic ductal adenocarcinoma (PDAC) to encapsulate and deliver
Stimulator of Interferon Gene (STING) and Toll-Like Receptor (TLR)4
agonists}~\cite{113}. {The authors showed that combining localized
immune agonist delivery with systemic tumor-targeted therapy could
coordinate innate and adaptive immune responses with durable anti-tumor
efficacy in PDAC. These very promising results obtained using syngeneic
transplant and autochthonous PDAC mouse models deserve much attention
for future applications.} 


{NPs were also applied to correct some lysosome defects that frequently
occur in inflammatory, autoimmune, neurodegenerative, and metabolic
diseases, as well as in cancer}~\cite{114}. {In the case of Parkinson's
disease (PD), acidifying NPs have been shown to slow neuron death in a
mouse model of the disease}~\cite{115}. {These NPs corrected the pH of
lysosomes within dopaminergic neurons, which are the first to be
affected by PD. In the case of cancer, different strategies utilizing
diverse types of NPs} {have also been described to treat tumors by
destroying lysosomes or realizing lysosomal escape}~\cite{116}.
{LAMP1-SPIONs (LAMP1 plays important roles in lysosome biogenesis,
lysosomal pH regulation, autophagy, and cholesterol homeostasis) induced
exosmosis of lysosome contents, meaning they move from the inside of
the vesicle, across the semipermeable lysosomal membrane, to the
external medium, for example, the cytoplasm. This leads to a decrease in
intracellular pH, which would eventually cause apoptosis}~\cite{117}.
{Other applications of NPs toward lysosomes are detailed 
by Tian et~al.}~\cite{116}. {These lysosome-oriented strategies are extremely
promising since in recent years,} {lysosomal changes and dysfunction
have been correlated with the development of numerous diseases, which
has led researchers and developers to propose that targeting lysosomes
in human diseases may represent a novel therapeutic way of
intervention}~\cite{114,118}.


{One of the most complicated challenges in the field of NPs is their
passage through the BBB. Some studies based on phytochemicals have
shown that NPs not only improve the pharmacological effect of these
substances but also enable targeting the brain and crossing of the
BBB. Various ligands were added to NPs to improve BBB transportation,
and, for example, a potential to protect against key features of PD was
observed, including ${\rmalpha}$-synuclein aggregation, mitochondrial
dysfunction, and dopaminergic neuronal death}~\cite{119}.

Many more examples of successful results may illustrate the importance
of NP-based strategies in immunotherapy. An important message that
emerges from these studies is that they have all required a meticulous
analysis of all the parameters, on a case-by-case basis. No global
recipe is applicable, and only experimentation has made it possible to
identify the best conditions (type of NPs, administration kinetics,
route and frequency of injections, timetable, etc.). Slight adjustments
in ligand graft density or encapsulation, the length of the
ligand--membrane linker, its nature, and all kinds of such parameters can
significantly influence interaction with the ligand receptor and
consequently the effectiveness of the loaded NP. 


{An important aspect is also to avoid any problem of immunogenicity of
the NP construct}~\cite{38}. {It is effectively of prime importance to
develop NPs that are ``furtive'' with regard to the immune system of
the recipient. Anti-drug antibodies (ADAs) that can appear with time in
treated individuals may inactivate the drug (e.g., a protein, a
therapeutic antibody, a peptide, a small molecule, or a nucleic acid
grafted on an NP) and cause a loss of targeting and/or an increased
clearance of ADA--drug complexes, which may lead to suboptimal exposure
and loss of efficacy. Therefore, ADAs represent a real challenge in
pharmacology as they affect pharmacokinetics, patient safety, and
treatment efficacy. Special attention should be given to this
troublemaker, especially as the person being treated has a defective
immune system that is difficult to control.} 

\section{Perspectives and limitations}

{NP-based delivery systems hold immense promise for targeted drug
delivery and enhanced therapeutic efficacy. However, their approval for
clinical use is fraught with significant challenges. It is well known
that NP physico-chemical properties influence their behavior}
in~vivo {and specifically their bio--nano interactions such
as protein opsonization, crossing barriers, and entering the target
organ and cells. In all these steps, any unpredicted interaction could
lead to unintended toxic effects. In principle, each pathway is
regulated by a constant rate. Therefore, knowing the constants, NPs
should be designed in accordance for better endocytosis and
clearance}~\cite{120}. {However, one primary concern is related to the
long-term toxicity of NPs when they are not rapidly excreted.
Commonly, the renal clearance of NPs is very efficient and fast with
NPs smaller than 10 nm, while limited clearance occurs with larger NPs
(${\sim}$100 nm). Despite the huge advances in using different
carriers, the nanomedicine field is still lacking in a consensual
understanding on how nanomaterials interact with human cells,
particularly immune cells to improve their biocompatibility and
safety}~\cite{17}. 

{Targeting the desired cells is another clinical issue. Nowadays, most
of the NPs approved for cancer reduce the toxicological profile of
drug agents rather than enhance the drug therapeutic efficacy. 
Poor delivery is one of the problems for translating
nanomedicine}~\cite{121}. {Wilhelm et~al.\ showed that ${<}$1\% of
NPs reach the tumor site}~\cite{122} {and similarly, it was
demonstrated that mRNA encapsulated LNPs are internalized by only 2\%
of T-cells}~\cite{123}. {To improve the selectivity, NP surface
decoration is the main strategy. However, some considerations have been
reported. The first one is related to the protein corona formation,
which can mask the ligands attached to the NP surface, decreasing the
binding with its receptor}~\cite{124}. {Second, the number and the
right orientation of appendix moieties can affect receptor
recognition}~\cite{125,126}. {Another central aspect that should be
considered is scaling up production. Complex multifunctional
formulations require multistep validations of the single components,
which is acceptable in a research lab but difficult to maintain in
industrial settings}~\cite{123}. {This can result in batch-to-batch
variability, impacting both the safety and efficacy of the final
product. Scaling up from a pilot plan to large-scale production remains
a significant milestone for any manufacturing company and developers.
Finally, to be clinically translated, NP syntheses and all their
components (external and internal molecules) should be prepared in good
manufacturing practice conditions, extending the production period of
registered clinical batches and increasing exponentially their cost.} 

Regarding ATMP monitoring, the prospects are
mainly in terms of
improving their safety, with the hope that the dose reduction through
quantification will also lead to lower costs. Currently, these costs
are manageable only for patients/healthcare systems that can afford
them. Unfortunately, these treatments
are not available to everyone. These two parameters (improved safety
and reduced costs) are in line with value-based healthcare, a
patient-centered approach to healthcare delivery
(\url{https://gestions-hospitalieres.fr/value-based-healthcare/}). It
aims to improve the health outcomes that matter most to patients---and
reducing side effects is certainly one of them---throughout their care
pathway, while optimizing healthcare resources and the cost to society.
Philosophical value and cost containment are both important, but
improving health outcomes is essential to creating value in a holistic,
systemic approach.

The main limitation of all these tracking and/or theranostic tools
remains on the side of regulatory affairs: how to qualify an ATMP
tracking tool, and how to qualify the combination of a tracking tool
being internalized in an innovative therapy? What is the qualification for a
magnetic hyperthermia therapy derived from an external stimulus
internalized in a cargo cell, which can itself interact with its
environment? 


{In terms of perspectives in the theranostic area, the difficulty of
active targeting tends toward ``cellular
nanotheranostics''}~\cite{127}, {that is, the use of cargo cells to deliver
theranostic NPs in sufficient quantity for a long-term effect
coupled with a drastic reduction in side effects.} 

\section{Conclusion}

In this review, we presented an overview about NPs, their types,
synthesis, characterization, physico-chemical properties, and potential
applications in health and diseases. Through different selected
\mbox{examples,} we described some successful results in different areas, such
as drug delivery, cell therapy tracking, and theranostics. This review
is not exhaustive; it covers only a small part of the field. Our aim
was not only to point out the success of NP-based strategies,
especially very recent ones, but also to insist on some concerns that
persist, especially due to the versatility and flexibility of NPs,
which is a strong point but can also be a difficult aspect to manage
for specific applications. Some aspects of safety were also
illustrated. After several decades of research and development, the
field of NPs is still constantly evolving. NPs continue to possess 
tremendous potential for innovation and societal impact. There is no
doubt that in the very near future, unsuspected developments of NPs
will emerge with the advent and widespread use of new technologies,
particularly in the field of miniaturization and implants, microfluidic
and flow chemistry technologies, and intradermal, intranasal, and
cerebral administration, to cite just a few. 

\section*{Declaration of interests}

The authors do not work for, advise, own shares in, or receive funds
from any organization that could benefit from this article, and have
declared no affiliations other than their research organizations.

\section*{Acknowledgments}
DFF would like to thank the Centre National de la Recherche
Scientifique (CNRS), the University of Strasbourg (UNISTRA), and all the
historical supports of the research carried out at the Institut de
Physique et Chimie des Mat\'{e}riaux de Strasbourg, namely, the
R\'{e}gion Grand Est, the Agence Nationale pour la Recherche (ANR),
Interreg IV Rhin Sup\'{e}rieur, and the Labex Nanoparticles in
Interaction with their Environment (NIE). 
SM acknowledges the support
of CNRS, the University of Strasbourg Institute for Advanced Study
(USIAS), the Interdisciplinary Thematic Institute IMS, as part of the
ITI 2021-2028 program of UNISTRA, CNRS and Inserm (ANR-10-IDEX-0002),
and SFRI (STRAT'US project, ANR-20-SFRI-0012), the French National
Agency for research (ANR-21-CE17-0026), the European Union's Regional
Development Fund in the context of the Interreg V Upper Rhine
program, the FHU ARRIMAGE, and the OMAGE projects funded by Region
Grand-Est and FEDER.

\CDRGrant[ANR]{ANR-10-IDEX-0002}
\CDRGrant[ANR]{ANR-20-SFRI-0012}
\CDRGrant[ANR]{ANR-21-CE17-0026}

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