Journal of Controlled Release 337 (2021) 494–504

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Journal of Controlled Release

journal homepage: www.elsevier.com/locate/jconrel

Review article

Advance cardiac nanomedicine by targeting the pathophysiological

characteristics of heart failure
Congcong Lin a, b, Huile Gao c, *, Liang Ouyang a, *
a
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu 610041,
China
b
Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Harbin 150081, China
c
Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, 610041, China

A R T I C L E I N F O A B S T R A C T

Keywords: Heart failure (HF) has continued to be a leading cause of morbidity and mortality worldwide. Nanomedicine,
Cardiac nanomedicine which can deliver therapeutic drugs/biomolecules specifically to damaged myocardium and overcome the
Targeted drug delivery limitations of conventional therapies, shows great potential in the treatment of HF. Although a number of
Biological barriers
preclinical studies of cardiac nanoformulations have been published, targeted nanomedicine for HF is yet to be
Pathophysiological changes
Heart failure
applied in clinical practice. Therefore, it is meaningful to sum up past experiences and deepen the understanding
of nanomedicine and HF. In this review, we first emphasized the key biological barriers to cardiac nanomedicine
that hinder its targeting effect. Since the rational design of nanoparticles should take into account the specific
characteristics of HF, we then summarized the key pathophysiological changes of HF to provide a clear un­
derstanding on HF, as well as the latest examples of nanotechnology-based delivery strategies for different
pathophysiological characteristics. Finally, the major challenges are discussed in detail, aiming to provide
guidance for future development of cardiac nanomedicine.

1. Introduction these beneficial effects in the application of nanoparticles, the clinical

HF is a heterogeneous and complex syndrome that results from
impairment of cardiac structure and function [1]. Although important
advances have been made in HF treatment, it remains a dominant cause
of death worldwide. Conventional methods including dilation of blood
vessels, limiting inflammation and the use of antithrombotic measures
are far from optimal, resulting in a 5-year mortality rate of up to 50%,
even 2–3 times that of breast cancer, colorectal cancer and other ma­
lignant tumors [2,3]. It is worth noting that by 2030, the prevalence of
HF is expected to increase by 46%, by then 1 in 33 Americans will suffer
from HF [4,5]. Therefore, alternative therapies such as nanomedicine
have been sought after in recent years.
As the forefront of life sciences, nanomedicine represents a prom­
ising approach for health care [6]. In line with this, over 100 nano­
medicine applications and products have been approved by the U.S.
Food and Drug Administration (FDA) [7]. For delivery purposes, nano­
medicine has multiple advantageous properties such as drug protection
from systemic degradation, controlled and sustained release of payloads,
tissue targeting and reduced secondary effects [8]. However, despite
translation of nanomedicine for the treatment of cardiac diseases is still
on the way. As such, summarizing the previous experiences and deep­
ening the knowledge of nanomedicine and HF are necessary, which may
contribute to finding innovative solutions to meet the current challenges
in the treatment of HF.
HF is not so much a disease as a pathophysiological state caused by
myocardial injury. Following myocardial injury, a network involving
molecular, cellular and structural mechanisms is activated to maintain
the physiological function [9]. These coordinated, complicated pro­
cesses accompanied with a series of pathophysiological changes
including activated oxidative stress, aberrant extracellular matrix
(ECM), overloaded intracellular calcium and activated immune system.
In view of this, it has great potential for the treatment of HF in response
to the key physiological changes caused by HF. Such potential can be
further fueled by nanotechnology-based delivery strategy that allows
targeted delivery of payloads to pathological areas. Besides, these
pathophysiological alterations that distinguish diseases and healthy
parts can serve as biological stimuli to “turn on” nanomedicine in the
body so that the nanomedicine can only provide its therapeutic effect on

* Corresponding authors.
E-mail addresses: gaohuile@scu.edu.cn (H. Gao), ouyangliang@scu.edu.cn (L. Ouyang).

https://doi.org/10.1016/j.jconrel.2021.08.002
Received 24 May 2021; Received in revised form 2 August 2021; Accepted 2 August 2021
Available online 4 August 2021
0168-3659/© 2021 Elsevier B.V. All rights reserved.
C. Lin et al.
the pathological site.
In this review, we focus on the advances in cardiac nanomedicine
oriented to the pathophysiological characteristics of HF. The review
begins by discussing the key biological barriers of nanomedicine for HF,
and the directions of nanocarrier design are highlighted. On this basis,
the recent advances in the development of cardiac nanomedicine that
target the key pathophysiological properties of HF are reviewed and
finally the major challenges are proposed. Through such a compact re­
view, we anticipate to afford a meaningful platform for better HF
treatment and further nanomedicine research.
2. Key biological barriers of cardiac nanomedicine
Taking the advantage of nanotechnology, therapeutic agent can be
delivered to the injured heart in a targeted manner. It is imperative to
accumulate predominant biomolecules/drugs within the target site for a
successful targeted delivery system [10,11]. In this regard, the pur­
posefully designed nanosystems for HF have to overcome a complex
series of biological barriers on the journey from the circulatory system to
the heart. Mononuclear phagocyte system (MPS) opsonization, hemor­
heological limitations, contractile forces extravasation, and endosomal/
lysosomal degradation are the main biological barriers for cardiac
nanomedicine. In Fig. 1, the four key biological barriers and the po­
tential strategies to overcome these barriers were highlighted.
As an important part of the immune system, MPS is the first obstacle
to nanomedicine. Through the phagocytosis of MPS, nanoparticles can
be directly removed, thereby significantly reducing the number of
nanoparticles reaching the target. To reduce the recognition rate of MPS
and prolong the blood residence time, the most common solution is
coating the carrier with water-soluble polymers [12–14]. Polyethylene-
glycol (PEG) is a well-developed coating polymer for nanocarriers,
conferring good stealth against the MPS and low immunogenicity
[15–17]. PEGylated liposomal adenosine, for example, was prepared for
Fig. 1. Framework of biological barriers that nanomedicines encounter and the potential strategies to overcome the barrier.
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Journal of Controlled Release 337 (2021) 494–504
ischemia/reperfusion injury [18]. In this study, a prolonged circulation
time of PEGylated liposomal formulation was observed by labeling
adenosine with radioisotope. However, if the PEGylated formulation is
repeatedly injected during long-term treatment, the prolonged circula­
tion effect may disappear caused by the production of anti-PEG IgM
[19,20]. Researchers have been endeavor to overcome this challenging
dilemma of PEGylation, such as pre-infusion with high molecular weight
free PEG [21]. McSweeney et al. explored infusion of free PEG to satu­
rate anti-PEG antibodies (APA) in mice. They found that the circulation
time is effectively restored by infusion of 40 kDa free PEG without
causing excess humoral anti-PEG responses and toxicity. Alternatively,
the reaction of MPS to the surface charge of nanocarrier also offers cues
to extend residence time of nanocarrier in circulation [22]. Zwitterionic
materials such as poly (carboxybetaine) and poly (sulfobetaine) are
considered as substitutes of PEG because of their strong hydration ability
and strong resistance to nonspecific protein adsorption [23]. Another
robust top-down approach is cellular membrane coating. Red blood
cells, leukocytes cells or platelets, as carriers of long circulation in na­
ture, provide a platform for the design of the next generation of nano­
carriers [24–26].
After escaping the clearance of MPS, nanomedicine needs to be
effectively attached to the damaged heart. At this time, the fluid dy­
namics in blood vessels becomes the main factor affecting the possibility
of nanocarriers reaching the heart. The dynamics of a nanocarrier in
blood vessels is mainly relied on its size and geometry. As reported,
nanocarriers with diameters >200 nm retained readily in the liver and
spleen, while those <5 nm are filtered by the kidney [27]. On this basis,
nanocarriers may be prepared with diameters ranging from 5 to 200 nm,
making them ideal for long-lasting in circulation. Before extravasation,
the nanoparticles have to first move to the wall of endothelial cells. That
is to say, margination is the premise. Notably, as a muscular power
organ for pumping blood, the heart is the source of blood circulation
power. The speed of the heart pumping blood is amazing. It ejects blood
C. Lin et al.
at a speed of 8 m per second. Therefore, margination dynamics of
nanoparticles to endothelial walls is a specifically essential consider­
ation for the design of cardiac nanomedicine. Recent studies revealed
that the attachment rate of nanoparticles is related to the shear stress of
endothelial wall and geometry of circulatory system [28,29]. It also has
been reported that physical characteristics of nanoparticles such as the
size, shape and density affect their margination towards endothelium
[30]. Take the shape for example, researchers have shown that the
attachment of discoidal nanocarriers is 5-fold higher than spherical ones
[31]. For nonspherical nanocarriers, their lateral drifting velocity is
proportional to their aspect ratio, and they exhibit unique tumbling and
rolling activity. However, for spherical nanocarriers, they tend to flow
parallel to the vessel wall. As such, reimagining of nanoparticle geom­
etry departure from conventional spherical shapes is a promising
effective strategy for nanomedicine.
Subsequently, the cardiac nanomedicine should cross the endocar­
dium to further accumulate and remain in the injured heart. In contrast
with cancer, the window of the enhanced permeability and retention
(EPR) effect in HF is short-lived [32]. Additionally, the issues of EPR
effect including heterogeneity, lack of cellular specificity and limited
patient data have also attracted the researchers' attention. It is note­
worthy that subjected to the contractile forces, cardiomyocytes envi­
ronment tends to expel injected drugs, which comes to be another key
barrier for the retention of cardiac nanomedicines. These findings cast
doubt on the application of the EPR effect in nanomedicines of HF.
Therefore, alternative and complementary strategies to enhance the
permeability and retention of cardiac nanomedicines are explored. One
of the most attractive strategies to enhance the permeability and
retention of cardiac nanomedicines is active targeting. Active targeting
simply referred as “ligand-receptor interaction”, can enhance the ag­
gregation of nanoparticles at HF sites by cooperating with EPR effect.
The target can be used for HF targeted therapy should unique expressed
or at least overexpressed (e.g. CD13 and AT1) at the injured heart
relative to other part of body. From this perspective, identify more
specific receptors or proteins that can be employed in nanotherapy
targeting HF is urgently needed. Another controllable and intuitive
method is to design nanomedicines with adjustable shapes or sizes,
which have recently proven their superiority in enhancing permeability
and retention [33]. Typically, enzyme, pH, redox, temperature and light
are utilized to trigger the transformation of these formulations [34].
Regarding transformable nanomedicines, the triggering factor that ini­
tiates the transformation process is the dominant factor and should be
carefully designed. To ensure the conversion occurs at where it is
needed, the distribution and quantity of the specific trigger need to be
sufficient evaluated. Besides, the in vivo fate of the transformable for­
mulations also should be closely monitored.
Finally, the nanomedicine is expected to enter the damaged car­
diomyocytes and escape from the endosome/lysosome, thereby
releasing the cargo into the cytoplasm. Normally, the cellular membrane
traversal of nanoparticles is through endocytosis pathway [35]. The
exact endocytosis pathway varies with the size and surface modification
of nanoparticles [36]. For example, the endocytosis of cellular receptor
modified nanoparticles is achieved through the clathrin-mediated
endocytosis, while the caveolae-receptor modified nanoparticles inter­
nalize cells through the caveolae-mediated endocytosis pathway
[37–39]. The endocytosis of nanoparticles begins with engulfment in
membrane invagination, and then forms intracellular vesicles (endo­
somes). The early endosome matures into a late endosomal compart­
ment and finally fuses with lysosomes [40]. During this process, the pH
decreases from ~pH 6.5 in early endosome, down to ~pH 6.0 in late
endosome. In lysosome, the pH even down to ~pH 5.0, with abundant
enzyme to degrade the cargo [41]. That means, if the nanoparticles
failure to escape from the endo/lysosomal pathway, they will entrap and
degrade in lysosome, thus preventing the successful transport of the
cargo into the cytoplasm. Up to now, several endosomal escape mech­
anisms including membrane fusion, proton sponge effect, swelling and
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Journal of Controlled Release 337 (2021) 494–504
membrane destabilization have been proposed. Deepen the underlying
mechanism of endosomal escape and ultimately engineering nano­
particles capable of escape the endosomes are necessary.
3. Development of cardiac nanomedicine based on HF
pathophysiology
Notably, either ischemic or nonischemic HF is accompanied by a
series of pathophysiological responses including activated oxidative
stress, aberrant extracellular matrix (ECM), overloaded intracellular
calcium, and activated immune system. Under the guidance of the above
mentioned design principles, further development of nanomedicine
based on these specific pathophysiological characteristics may be a
promising direction for preventing the progresses of HF. In this section,
the key pathophysiological changes of HF are summarized and the latest
examples of nanotechnology-based delivery strategies targeting these
pathophysiological characteristics are reviewed (Fig. 2).
3.1. Nanomedicine targeting activated oxidative stress
Since ischemia is the most common cause of HF where blood flow
and oxygen supply interrupted, the damaged heart tends to be exposed
to a hypoxic condition [42]. As a consequence, the injured tissues/cells
show elevated oxidative stress. Oxidative stress is identified as an
extreme imbalance of “redox state” [43]. Under pathological condition,
high reactive oxygen species (ROS) are produced via various sources
including mitochondria, xanthine oxidase, NADPH oxidases and
uncoupled nitric oxide synthase (NOS) [44]. The excessive ROS can
activate apoptosis pathway and damage cell membrane and etc., thereby
affecting the growth, proliferation and metabolism of cardiomyocytes in
a variety of ways [45]. Therefore, strategies to minimize ROS of HF
patients are clinically important.
Endogenous/exogenous antioxidants are the first choice to deplete
the excessive ROS in HF. However, they are either “ too nonspecific, too
little, too late”, or they are related to the possible side effects [46–48].
To address these limitations, researchers have developed various
nanovactors including liposomes, micelles, polyamidoamine (PAMAM)
dendrimers and polymer nanoparticles to deliver these ROS scavengers
(Table 1). It is worth noting that the hypoxic condition in HF patients
enhances vascular permeability through the production of angiogenic
factors and the migration of endothelial cells [49]. As such, EPR effect, a
well-known concept in tumor nanotherapy, is also the most common
principle in the research field of HF nanomedicines [50]. Taking the
advantage of the disrupted endothelia wall, the nanoparticles can
passively pass through the blood vessels and endocardium, so that
relatively large doses of antioxidants are delivered to the damaged
myocardium [51]. Then exhibited their cardioprotective effects by in­
hibition of inflammation or triggering the cascades involved in the
antioxidant defense system. In this way, previously discarded antioxi­
dants for HF therapy may still prove useful and be worthy of re-
examination.
Since mitochondria are the main source of ROS, studies for the
elimination of mitochondrial ROS in cardiomyocytes is drawing more
attention for HF treatment in recent years. Taking the advantage of
mitochondria-targeting materials, such as small mitochondria-targeting
cationic peptides, triphenylphosphonium(TPP) and fusogenic lipid,
mitochondrial drug delivery can be achieved [52]. For instance, a smart
dual-shell polymeric nanoparticle (MCTD-NPs) using multistage
continuous targeted strategy to mitochondrial delivery of resveratrol
was fabricated (Fig. 3) [53]. In the study, ischemic myocardium targeted
peptide (IMTP) was conjugated with poly(lactic-co-glycolic acid)
(PLGA) via a long pH-responsive PEG chain to form outshell of the
nanoparticle, which reduced the recognition rate of MPS and prolonged
the blood residence time to enhance the accumulation in the ischemic
myocardium. At the same time, a positively charged polypeptide SS-31
was also modified on the nanoparticles to form an inner-shell, which
C. Lin et al. Journal of Controlled Release 337 (2021) 494–504

Fig. 2. A summary of key pathophysiological changes during HF, proposed therapeutic strategies and representative nanoparticle architectures for treatment of HF.

Table 1
Examples of nanomedicine targeting oxygen stress.
Nanovector Load drug Model of use Key result Ref

Liposome CoQ10 New Zealand white rabbits with Improved the intracellular delivery of CoQ10 and reduced the [57]
experimental MI infarction size
Guar gum nanoparticles Selenium Ischemic buffer induced H9c2 Protected H9c2 cells from I/R injury through improving the [58]
cells efficiency of mitochondrial electron transport chain
Pluronic F-127 micelle Resveratrol- Doxorubicin-induced Swiss Reduced the doxorubicin-induced ROS damage [59]
quercetin Webster mice
G4 PAMAM dendrimers S-nitroso-N- No-flow I/R ex vivo rat hearts Regulated the nitric oxide release and limited I/R injury [60]
acetylpenicillamine
Carboxymethyl chitosan Curcumin I/R injury rats Inhibited cardiomyocyte apoptosis and cardiac hypertrophy in rats, [61]
nanoparticles-peptide and improved the bioavailability
PLGA nanoparticle Quercetin Antimycin A challenged H9c2 Preservation of mitochondrial function and ATP synthesis, [62]
cells suppressed oxidative stress
PLA nanoparticle Curcumin-nisin Guinea pigs with isoproterenol Significant cardioprotection effect with no toxicity [63]
induced MI

could strongly bind to mitochondria and promote the nanoparticles to
escape lysosome. When entrapped in the acidic lysosomes, the hydrazine
bond on outshell of the nanoparticle broke rapidly, and then SS-31 is
exposed. In the mitochondria, resveratrol was released, showing
significantly reduction of fraction size in the myocardial ischemia-
reperfusion injury (MI/RI) rats. The precise delivery of antioxidants to
the ROS generation organelles provides a promising direction for scav­
enging excess ROS.
Apart from encapsulating antioxidant in nanovectors, nanovector
therapy is also a way to regulate the excess ROS. Some of the nano­
materials per se exhibiting antioxidant properties, like CeO2, have been
employed in HF targeted nanotherapy. In CeO2, Ce is Ce3+ and Ce4+
[54]. Under the mixed valences states, cerium particles can easily
change its electronic design and make it most suitable for the sur­
rounding environment through the rapid and convenient transformation
between Ce3+ and Ce4+. Shereen et al. synthesized a CeO2 nanoparticle
around 5 nm, which have the ideal size to overcome the above
mentioned limitations of hemorheology. After its treatment, the serum
cardiac markers including CK-MB, LDH, AST and ALT in isoproterenol-
induced myocardial infarction (MI) rats were noticeably decreased,
while the antioxidant enzymes level including catalase and superoxide
dismutase were increased [55]. Although the above mentioned study
provide a positive outcome for HF treatment, safety profiles of utilizing
this kind of metal oxide nanoparticle still need to be assessed.
ROS-responsive nanomedicine is another effective approach to
reduce the damage caused by oxidative stress. For instance, a H2O2-
triggered bubble-generating antioxidant polymeric nanoparticle for
hepatic I/R injury has been developed [56]. In the study, peroxalate
esters bond that can rapidly oxidize by H2O2 was introduced to form the
polymeric prodrug, poly(vanillin oxalate) (PVO). Once exposed to H2O2,
vanillyl alcohol was released from the PVO nanoparticles to exert its
anti-apoptotic and anti-inflammatory activities. Also as a H2O2-

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C. Lin et al.
Fig. 3. (A) Schematic image of precise treatment of MI/RI through multistage mitochondrial delivery of resveratrol by using MCTD-NPs; (B) Experimental protocols
for the in vivo rat MI/RI model; (C) Sections from left ventricle regions indicated in the artist's rendition were subjected to ex vivo distribution research; (D) Ex vivo
distribution of cy7.5 labeled PLGA-NPs and cy7.5 labeled MCTD-NPs in sham and MI/RI heart; (E) Ex vivo distribution of cy7.5 labeled PLGA-NPs and cy7.5 labeled
MCTD-NPs in four sections of MI/RI heart. Nanomedicine: nanotechnology, biology, and medicine. 2019;16:236–49. © Elsevier Inc.
associated disease, this PVO nanoparticle may be translated to treat HF.
As an attractive and viable direction, other ROS-responsive materials or
structure, such as thioester, phenylboronic ester and polypropylene
sulfide may also be explored in designing ROS-triggered cardiac nano­
medicines [33].
3.2. Nanomedicine targeting aberrant ECM
The myocardial ECM is a dynamically changing environment, which
is fundamental for the physiological homeostasis and structural of the
heart. In HF patients under oxidative stress, the ECM homeostasis is
disturbed by highly expressed extracellular matrix metalloproteinase
inducer (EMMPRIN) [64]. EMMPRIN not only active matrix metal­
loproteinases (MMPs), but also increase MMPs expression [65,66]. In
fact, the MMPs also exist under physiological conditions, but in an
inactive form. Once myocardial injury occurred, they become activated.
The activation and overexpression of MMPs results in collagen degra­
dation and thereby induces fibroblast proliferation [67]. Therefore,
inhibit the activation of EMMPRIN and MMPs to minimize the degra­
dation of cardiac ECM is a promising resolution to ameliorate HF
[68,69].
As mentioned above, EMMPRIN inhibition may point to a new
approach to migrate HF injury. Under this concept, Cervadoro A et al.
conjugated the paramagnetic/fluorescent micellar nanoparticles with
AP-9 peptide (NAP9), which can specifically bind with EMMPRIN. By
this active targeting strategy, the aggregation of NAP9 at HF sites was
enhanced and in turn prevented the MMP-mediated ECM degradation
and reduced the infarct size in mice [70]. The abnormal ECM can not
only be used as a therapeutic target, but also as an effective stimulus for
the design of HF targeted nanoparticles. A MMPs response morphology
transformable nanoparticle was fabricated using brush peptide-polymer
amphiphiles (PPAs) [71]. Interestingly, the peptide sequences PLGLAG
in PPAs can be specifically recognized by the upregulated MMPs, MMP-2
and MMP-9. After intravenous injection, the spherical enzyme-
responsive nanoparticles can circulate freely in the bloodstream until
they extravasate the leaky vascular system and reach the infarct site,
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Journal of Controlled Release 337 (2021) 494–504
where they discrete into network-like scaffolds. However, affected by
contractile force, the injected drugs tend to be expelled by the car­
diomyocyte environment. By this morphological transition strategy
based on MMPs response, the nanoparticles can remain in the injured
heart even be observed at day 28 post-injection (Fig. 4). Critically, the
study provided a useful platform with targeted accumulation and pro­
longed retention for MI therapy.
Encapsulate drugs/biomolecular in MMPs-responsive nanovectors
may achieve “on-demand” and localized drug release by utilizing MMPs
hyperactivation as a trigger. A dual functional MMPs-responsive
hydrogel was developed for basic fibroblast growth factor (bFGF)
localized release and MMPs inhibition to promote the recovery of MI
[72]. Although this hydrogel ameliorated myocardium remodeling and
enhanced vascularization by targeting upregulated MMPs, it is unlikely
that patients with weakened MI wall receiving intramyocardial admin­
istration given the safety concerns. Further studies to exploit systemi­
cally nanoparticle formulations targeting the upregulated MMPs are still
needed.
3.3. Nanomedicine targeting overloaded intracellular calcium
Ca2+ is essential for the activation of myofilaments and electrical
activity that enable contraction of heart. However, Ca2+ overload occurs
in patients with HF due to ischemia. Ischemia induced acidosis directly
increases the accumulation of Na+ through Na+/H+ exchanger (NHE),
and then transports Ca2+ into cells by reversing the function of Na+/
Ca2+ exchanger [73]. In addition, under oxidative stress, excess O2−
interacts with NO to form peroxynitrite, which triggers protein oxida­
tion that will further damage the excitation-contraction coupling [74].
In the case of excitation contraction coupling damaging, L-type calcium
channels, potassium channels, sodium channels and the Na+/Ca2+
exchanger are involved, directly resulting in Ca2+ overload in the
injured heart. Meanwhile, the sarcoplasmic reticulum Ca2+-adenosine
triphosphatase (SERCA) is altered and the calcium sensitivity of the
myofilaments is reduced [75,76]. Accordingly, HF patients may benefit
from targeting therapies of calcium mishandling.
C. Lin et al. Journal of Controlled Release 337 (2021) 494–504

Fig. 4. (A) Diagram of a dye-labeled brush peptide-polymer amphiphile (PPA) containing an MMP-2 and MMP-9 specific recognition sequence, shown underlined.
PPAs self-assemble into nanoparticles through hydrophobic-hydrophilic interactions when dialyzed into aqueous buffer. (B) Schematic of nanoparticles freely
circulating in the bloodstream (not to scale) upon systemic delivery. Nanoparticles enter the infarct tissue through the leaky acute MI vasculature, and upregulated
MMPs within the infarct induce the formation of an aggregate-like scaffold. (C) In vitro, responsive (top) and nonresponsive (bottom) nanoparticles are monodisperse
micelles with diameters of 15–20 nm, and (D) upon activation, only responsive nanoparticles form an aggregate-like scaffold. (E) Corresponding images of nano­
particle solutions following activation. (F) Dynamic light scattering of nanoparticles before and after MMP activation. (G) Retention of IV delivered nanoparticles
with the infarct. H&E images are shown in A, and neighboring fluorescent sections are shown in B. Particles are shown in red and myocardium. Scale bar: 100 μm.
Adv Mater. 2015 Oct 7;27(37):5547–52. © WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (For interpretation of the references to colour in this figure legend, the
reader is referred to the web version of this article.)

At present, the efficacy of calcium channel antagonists including L-
type Ca2+ channel antagonists, mitochondrial Ca2+ channel antagonists
and sarcolemma Ca2+ channel antagonists is often limited due to the
lack of solubility, bioavailability or specificity [77]. Using nanovactors
to target deliver the modulators of Ca2+, either to cardiac calcium
channels, or specifically to mitochondria, could be an exciting
development for HF therapy. Table 2 summarizes representative ex­
amples of the present nanotherapy strategies targeting intracellular
calcium overload. Additionally, a number of Ca2+ channel blockers such
as amiodarone, diltiazem hydrochloride and nitrendipine have
benefited from nanotechnology [18,78–81]. Take the class III antiar­
rhythmic drug amiodarone as an example. It has low solubility and acts

Table 2
Examples of nanomedicine targeting intracellular calcium overload.
Nanovector Load drug Model of use Key result Ref

Solid-lipid nanoparticle Nitrendipine In vitro Improved the effective bioavailability up to 2.81–5.35-folds greater [90]
than nitrendipine suspension
PEGylated liposome Amiodarone I/R injury rats Prolonged blood residence time and reduced the infarction size and [18,79]
mortality
Chitosan-coated Fe3O4 Omecamtive Mecarbil Male Wistar rats Improved the cardiac function with only 4% necessary dose of OM [84]
nanoparticle amount
GlcNAc-polyketal S100A1 Sprague-Dawley rats with Decreased the irregular calcium release through “two-hit” effect on [88]
nanoparticles nonischemic HF modulation of calcium regulation proteins
PLGA nanoparticle Cyclosporine A I/R injury mice Increased accumulation of cyclosporine A in myocardium [91]
mitochondria and limited HF progression via preventing mPTP-
opening
Polymeric nanoparticle alpha-interacting domain I/R ex vivo rat hearts Decreased oxidative stress and superoxide production in cardiac [92]
peptide- curcumin myocytes, reduced muscle damage
CaP nanoparticle mimetic peptide Rodent models of diabetic Improved myocardial contraction and in turn restored cardiac [6]
cardiomyopathy (mice, rats, pigs) function via inhalation of this peptide-loaded nanoparticles

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on many ion channels of myocardium and vascular smooth muscle [82].
To improve its solubility and reduce its acute toxicity, a nanosuspension
of amiodarone was prepared [78]. PEGylated liposomes of amiodarone
also have been developed [18,79]. In the I/R rats, the liposomal amio­
darone with prolonged blood residence time significantly reduced the
infarct size (29.5 ± 6.5%) compared to the control (53.2 ± 3.5%), and
reduced the mortality due to the negative hemodynamic and lethal
arrhythmia caused by adenosine.
Instead of reducing the calcium flux, improving the calcium sensi­
tivity of myofilament is also a practical strategy for the treatment of HF.
Omecamtive Mecarbil (OM) is a novel Ca2+ sensitizing positive inotrope
for the treatment of systolic HF [83]. Dose-dependent side effects and
repeated administration are the major downside for the use of OM. To
tackle these problems, a chitosan-coated magnetic Fe3O4 nanoparticle
was developed for OM heart targeting delivery in a very recent study
[84]. The cationic nature and hydrophilicity of chitosan helped to avoid
opsonization of the MPS and increased the colloidal stability of the
Fe3O4 nanoparticles. Fe3O4 nanoparticles, also referred as surperpar­
amagnetic iron oxide nanoparticles (SPIONs), not only conferred
biocompatibility and safety of the nanoparticles but also the therapeutic
effect on patients with low-risk MI [85]. A single dose injection con­
taining 510 mg SPIONs significantly lowered end systolic volume (ESV)
and increased the ejection fraction (EF) from 53 to 59%. In addition,
SPIONs also take part in increasing the formation of mitochondrial ATP
and improving the survival of cardiomyocytes. As a result, by this tar­
geting strategy, the OM dose was reduced to 4% of the traditional dose,
and EF was improved by 18%. This study highlights the prospective of
developing SPIONs for HF treatment in which synergistic effects can be
achieved.
To further improve targeting efficacy, the specific targeting moieties
was also introduced into the design of nanotherapy targeting intracel­
lular calcium overload. N-Acetylglucosamine (GlcNAc), a sugar with
high affinity for cardiomyocytes has aroused the interest of researchers
[86]. Decoration of GlcNAc on the surfaces of nanoparticles increased
their uptake by cardiomyocytes. Furthermore, in cardiomyocytes, O-
GlcNAc transferase catalyzes the GlcNAc attachment to threonine or
serine residues of key intracellular Ca2+ regulating proteins such as
SERCA2a, STIM1, PLB and CaMKII [87]. In a recent study, GlcNAc was
conjugated on the surface of biodegradable polyketal nanoparticles for
S100A1 delivery [88]. S100A1 is a Ca2+-binding protein, which also can
interact with the calcium regulation proteins like SERCA2a to modulate
myocardial contraction [89]. This GlcNAc nanoparticles carrying
S100A1 protein demonstrated a “two-hit” effect on modulation of cal­
cium regulation proteins, contributing for the reduction of abnormal
calcium release and the recovery of sarcomere function. This study of­
fers new insights into the development of bioactive nanovectors to
optimize therapies.
3.4. Nanomedicine targeting immune activation
As a defense mechanism, innate immune system activation is a
protective response to myocardial injury, in which the inflammatory
cells and mediators work in tandem. Generally, the very early healing
processes are initiated by leucocytes infiltrating to remove irreparably
damaged cells. Other inflammatory cells including neutrophils and
macrophages are also considered to be essential components for infarct
area repair [93]. Neutrophils orchestrate the healing process through
polarizing macrophages from M1 to M2 [94]. It has been validated that
M1 macrophages active the pro-inflammatory pathway, while in
contrast, M2 macrophages induce anti-inflammatory pathways and
exhibit cardiac repair ability [95]. Apart from cellular immune response,
recent evidence also highlights the potential role of inflammatory me­
diators and their interactions in driving HF progress [96]. In HF,
accelerated concentrations of pro-inflammatory cytokines including
tumor necrosis factor α (TNFα), interleukin 1 (IL-1) and 6 (IL-6) are
observed. The production of TNFα, IL-1 and -6 can be downregulated by
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Journal of Controlled Release 337 (2021) 494–504
the anti-inflammatory cytokine IL-10 and transforming growth factor β
(TGFβ). Therapy strategies to judiciously regulate the polarization of
macrophages and cytokines production may help alleviate damage of
HF. In recent years, nanoimmunotherapy has been an increasingly
popular approach in nanomedicine. Using nanomedicine or surface
functionalized nanomaterials to judiciously regulate the polarization of
macrophages and cytokines production may help alleviate damage of
HF.
Modulation of macrophage polarization to a reparative state is a
promising approach to elicit infarct repair and promote resolution of
inflammation. Notably, nanoparticles composed of polyurethane (PU)
were found to induce the polarization of macrophage to M2, which
suppress the activation of inflammasome signals and NF-κB, and in turn
reduce the production of inflammatory cytokines like IL-1β and TNF-α
[97]. Owing to its excellent elastic properties, the biodegradable PU is
gaining attention in recent years. Exploring more nanomaterials like PU
nanoparticle can be a potential therapeutic nanovector for HF
immunomodulation.
In another case, phosphatidylserine (PS)-presenting liposomes were
intravenously injected to modulate cardiac macrophages and improve
infract repair of MI rats [98]. The strategy was designed based on the
underlying principle of anti-inflammatory effects of apoptotic cells. As
known, PS is identified as a “death signal” of cells, which can be
recognized by macrophages via the PS receptor. PS presenting on the
surface of liposomes skillfully mimicked the anti-inflammatory effects of
apoptotic cells. After the “mimic apoptotic cells” uptake by macro­
phages, anti-inflammatory cytokines TGFβ and IL-10 were secreted,
while the pro-inflammatory markers such as TNFα and CD86 were
downregulated. As a consequent, this strategy promoted the preserva­
tion of small scars and angiogenesis, and prevented ventricular remod­
eling. This ingenious strategy provides a candidate platform for immune
response modulating and HF nanoimmunotherapy.
Another possible immunomodulation strategy is to directly regulate
the production of cytokines. Among the cytokines of HF, the key pro-
inflammatory marker, TNFα has been extensively studied and is found
to be a potential therapeutic target. As such, deoxyribozyme (DNAzyme)
functionalized gold nanoparticle (AuNPs) was fabricated to catalytically
silence TNFα for MI [99]. After local injection of this DNAzyme AuNPs in
the myocardium of MI rats, the TNFα knockdown efficiency achieved as
high as 50%, which subsequently resulted in noticeable improvement in
acute cardiac function. The study represents an example of the use of
DNAzyme AuNP conjugates for gene regulation and viable delivery.
Similar approaches in regulating the immune environment and
improving the treatment of HF will be an exciting development.
4. Major challenges of cardiac nanomedicine
Despite the encouraging results, there are still many challenges to be
solved and further optimized before cardiac nanomedicine can be
transformed into viable clinical products. In this section, the major
challenges including the formation of the protein corona, off-target ef­
fect, safety warnings and potential adverse effects are listed and
discussed.
One of the central challenges in targeted nanomedicine is the for­
mation of the protein corona. Once the nanocarrier enters the circula­
tory system, they are wrapped in proteins in a process called
opsonization, marking that they are phagocytized by MPS then cleared
from the body. In particularly, the protein mentioned here has been
extensively studied for a decade, which is termed as protein corona
[100]. As reported, when in contact with biological fluids, different
types of proteins are adsorbed on nanoparticles to form protein corona.
The protein corona can substantially affect the biological fate of nano­
carriers, such as increasing uptake by the MPS [101–103]. In addition to
mediating the uptake of MPS, protein corona has also been shown to be
detrimental to active targeting strategies [104,105]. The specificity of
the targeted ligand will be significantly reduced due to the covering of
C. Lin et al.
the attached biological corona [106]. For example, it was demonstrated
that transferrin-modified silica nanoparticles lost the targeting ability
after incubation with plasma [107]. Although researchers have made
numerous efforts, few effective strategies have been proposed to mini­
mize the mistargeting caused by corona. Among which, coating zwit­
terionic compounds on the surface of nanoparticles is validated to be a
potential strategy. For instance, corona-free Au nanoparticles have been
fabricated by a range of zwitterionic coatings [108].
Cardiac nanomedicine is designed to specifically deliver the drug/
biomolecule to injured heart and enhance their accumulation. However,
the off-target effect always occurs, which attenuates their efficacy. On
the one hand, this is because HF is a progressive disease with complexed
and changeable pathological state. For example, following MI, the heart
first subjects to an early inflammatory phase (phase 1) with pro-
inflammatory cytokines such as IL-1β and TNF-α released, when turns
to inflammation resolution stage (phase 2), the anti-inflammatory cy­
tokines IL-10 and TNF-β are secreted. In this regard, time selection has
become a non-negligible factor in the selection of different targeting
strategies for the treatment of HF. On the other hand, as mentioned
previously, ligand-receptor binding is the most effective and commonly
used targeting strategy in nanotherapy to help target damaged car­
diomyocytes. However, the intrinsic structure of ligands may be
destroyed by chemical modification, resulting in the decrease of binding
efficiency [109]. The emerging of bio-orthogonal reactions provides a
potential resolution to avoid the off-target effects, in which the second
tag can specifically identify the labeled cells by labeling the target cells
with a primary exogenous tag first [110–112]. However, the related
research only stays at the cellular level, and further efforts are needed to
make it better applied in vivo.
Last but not least, safety warnings and potential adverse effects are
also the main concerns for the application of nanomedicine in cardiac
disease. For instance, recent studies have shown that iron compounds
can induce ferroptosis in the presence of ROS, a newly discovered pro­
grammed cell death form associated with I/R injury [113–115]. Fenton
reaction (i.e., the process of converting hydrogen peroxide to hydroxyl
radicals)/iron metabolism leads to excessive production of ROS,
resulting in regulatory cell death [116,117]. These findings challenge
the use of iron-based nanoparticles and remind experts to be more
cautious in choosing the composition of nanoparticles. In addition, it is
essential to evaluate the biological fate and safety profiles of nonde­
gradable inorganic nanoparticles for long-term use. Recent studies have
shown that polymeric-coated Au nanoparticles could be degraded by the
liver proteolytic enzymes [118]. This suggests that the physicochemical
properties of the nanoparticles may alteration in vivo, resulting in un­
necessary or unpredictable toxicity, aggregation or immune activation.
The changes of physical and chemical properties of nanoparticles in­
crease the complexity of host immune system inflammatory response,
which may take along more adverse effects on HF process than expected.
Therefore, it is necessary to study the biological fate of nanoparticles
more carefully.
5. Conclusions and future perspectives
In decades, a number of studies have been carried out to limit the
damage of HF by addressing their pathological mechanisms. Indeed, the
therapies have shown their potential in animal models. However, many
of them have limited bioavailability and poor specificity, which leads to
their failure in clinical trials. As shown in this review, cardiac nano­
medicines have circumvented many limitations of traditional therapies
by improving drug accumulation in injured cardiomyocytes, and
reducing unwanted side effects and systemic dosage. In particular, in
recent years, intelligent and on-demand delivery nanomedicine have
further been developed according to the unique pathological environ­
ment of HF to achieve accurate local drug release. With the application
of nanotechnology in the control of biological systems, diagnosis,
treatment and monitoring of diseases, the development of cardiac
501
Journal of Controlled Release 337 (2021) 494–504
nanomedicine goes beyond the concept of “magic particulate bullet”
[119]. Nowadays, cardiac nanomedicine is not limited to nanoparticles
and the technology to evaluate their application in the body, but also
involves the design of new scaffolds (i.e. nanorods) to enhance thera­
peutic cells' engraftment in myocardial tissue and surfaces for engi­
neering sensors to identify HF biomarkers (i.e. nanosheets) or
implantable devices to aid in the regeneration of tissues (i.e. carbon
nanotubes) [120–123]. Although many of these concepts are still in the
early stages of development, the application of nanotechnology has
brought great benefits to the significant increase in bioavailability and
specificity. Taking the advantage of nanotechnology, therapies by
addressing pathological mechanisms of HF are being the most promising
approaches to prevent the progression of HF.
Although nanotechnology has made great progress in the treatment
of HF, the application of cardiac nanomedicine in patients is still in its
infancy. By settling each of the existing challenges in turn and
combining innovative design functions reasonably, effective nano­
medicine for HF will definitely be developed, thereby realizing a para­
digm shift of therapy delivery based on nanoparticles. For future study,
researchers should carefully learn from the lessons of cancer nano­
technology, such as by reporting the basic information required (e.g.,
physicochemical properties of nanoparticles, detailed information on
the biological interface of nanoparticles, biological properties of nano­
particles, and complete information about biological systems). Addi­
tionally, development of cardiac nanomedicine requires coordinating
and connecting multiple fields, including molecular and cellular
biology, chemistry and biochemistry, cardiology and materials sciences,
among others. In this regard, build a strong bridge between experts in
the field of cardiac nanotechnology is essential importance.
Declaration of Competing Interest
The authors have no conflict of interest to declare.
Acknowledgements
The authors gratefully acknowledge the financial support from
Natural Science Foundation of Heilongjiang Province of China (No.
YQ2019H004), Post-Doctor Research Project of West China Hospital of
Sichuan University (No. 2020HXBH172), 111 project (No. B18035) and
Excellent Yong Talents Funding of College of Pharmacy of Harbin
Medical University (No. 2019YQ07).
References
[1] E. Tanai, S. Frantz, Pathophysiology of heart failure, Comprehensive Physiol.
(2015) 187–214.
[2] M. Iafisco, A. Alogna, M. Miragoli, D. Catalucci, Cardiovascular nanomedicine:
the route ahead, Nanomedicine (London) 14 (2019) 2391–2394.
[3] H. Dokainish, K. Teo, J. Zhu, A. Roy, K.F. AlHabib, A. ElSayed, et al., Global
mortality variations in patients with heart failure: results from the international
congestive heart failure (INTER-CHF) prospective cohort study, Lancet Glob.
Health 5 (2017) e665-e72.
[4] S.S. Virani, A. Alonso, E.J. Benjamin, M.S. Bittencourt, C.W. Callaway, A.
P. Carson, et al., Heart disease and stroke statistics-2020 update: a report from the
American heart association, Circulation. 141 (2020) e139–e596.
[5] D. Snipelisky, S.P. Chaudhry, G.C. Stewart, The many faces of heart failure,
Cardiac electrophysiology clinics. 11 (2019) 11–20.
[6] M. Miragoli, P. Ceriotti, M. Iafisco, M. Vacchiano, N. Salvarani, A. Alogna, et al.,
Inhalation of peptide-loaded nanoparticles improves heart failure, Sci. Transl.
Med. 10 (2018).
[7] F. Farjadian, A. Ghasemi, O. Gohari, A. Roointan, M. Karimi, M.R. Hamblin,
Nanopharmaceuticals and nanomedicines currently on the market: challenges
and opportunities, Nanomedicine (London) 14 (2019) 93–126.
[8] V.M. Martin Gimenez, D.E. Kassuha, W. Manucha, Nanomedicine applied to
cardiovascular diseases: latest developments, Ther. Adv. Cardiovasc. Dis. 11
(2017) 133–142.
[9] G.M. Felker, L.K. Shaw, C.M. O’Connor, A standardized definition of ischemic
cardiomyopathy for use in clinical research, J. Am. Coll. Cardiol. 39 (2002)
210–218.
C. Lin et al.
[10] L.C. Ou, S. Zhong, J.S. Ou, J.W. Tian, Application of targeted therapy strategies
with nanomedicine delivery for atherosclerosis, Acta Pharmacol. Sin. 42 (1)
(2021) 10–17.
[11] F. Shakeel, Recent advances in liposomal drug delivery system for drug targeting,
Current drug delivery. 17 (2020) 824–825.
[12] S.M. Moghimi, A.C. Hunter, J.C. Murray, Long-circulating and target-specific
nanoparticles: theory to practice, Pharmacol. Rev. 53 (2001) 283–318.
[13] V.P. Torchilin, Polymer-coated long-circulating microparticulate
pharmaceuticals, J. Microencapsul. 15 (1998) 1–19.
[14] Y. Sheng, C. Liu, Y. Yuan, X. Tao, F. Yang, X. Shan, et al., Long-circulating
polymeric nanoparticles bearing a combinatorial coating of PEG and water-
soluble chitosan, Biomaterials. 30 (2009) 2340–2348.
[15] J.V. Jokerst, T. Lobovkina, R.N. Zare, S.S. Gambhir, Nanoparticle PEGylation for
imaging and therapy, Nanomedicine (London) 6 (2011) 715–728.
[16] M. Kanamala, B.D. Palmer, H. Ghandehari, W.R. Wilson, Z. Wu, PEG-
benzaldehyde-hydrazone-lipid based PEG-dheddable pH-sensitive liposomes:
abilities for endosomal escape and long circulation, Pharm. Res. 35 (2018) 154.
[17] S. Mustafa, V.K. Devi, R.S. Pai, Effect of PEG and water-soluble chitosan coating
on moxifloxacin-loaded PLGA long-circulating nanoparticles, Drug delivery and
translational research. 7 (2017) 27–36.
[18] H. Takahama, T. Minamino, H. Asanuma, M. Fujita, T. Asai, M. Wakeno, et al.,
Prolonged targeting of ischemic/reperfused myocardium by liposomal adenosine
augments cardioprotection in rats, J. Am. Coll. Cardiol. 53 (2009) 709–717.
[19] H. Xu, K.Q. Wang, W.W. Huang, Y.H. Deng, D.W. Chen, Recent advances in the
study of accelerated blood clearance phenomenon of PEGylated liposomes, Acta
Pharm. Sin. 45 (2010) 677–683.
[20] M.M. El Sayed, H. Takata, T. Shimizu, Y. Kawaguchi, A.S. Abu Lila, N.E. Elsadek,
et al., Hepatosplenic phagocytic cells indirectly contribute to anti-PEG IgM
production in the accelerated blood clearance (ABC) phenomenon against
PEGylated liposomes: appearance of an unexplained mechanism in the ABC
phenomenon, J. Control. Release 323 (2020) 102–109.
[21] M.D. McSweeney, L.S.L. Price, T. Wessler, E.C. Ciociola, L.B. Herity, J.
A. Piscitelli, et al., Overcoming anti-PEG antibody mediated accelerated blood
clearance of PEGylated liposomes by pre-infusion with high molecular weight
free PEG, J. Control. Release 311–312 (2019) 138–146.
[22] S. Jiang, Z. Cao, Ultralow-fouling, functionalizable, and hydrolyzable zwitterionic
materials and their derivatives for biological applications, Adv. Mater. 22 (2010)
920–932.
[23] W. Yang, L. Zhang, S. Wang, A.D. White, S. Jiang, Functionalizable and ultra
stable nanoparticles coated with zwitterionic poly(carboxybetaine) in undiluted
blood serum, Biomaterials. 30 (2009) 5617–5621.
[24] J.O. Martinez, R. Molinaro, K.A. Hartman, C. Boada, R. Sukhovershin, E. De Rosa,
et al., Biomimetic nanoparticles with enhanced affinity towards activated
endothelium as versatile tools for theranostic drug delivery, Theranostics. 8
(2018) 1131–1145.
[25] C.M. Hu, L. Zhang, S. Aryal, C. Cheung, R.H. Fang, L. Zhang, Erythrocyte
membrane-camouflaged polymeric nanoparticles as a biomimetic delivery
platform, Proc. Natl. Acad. Sci. U. S. A. 108 (2011) 10980–10985.
[26] C.M. Hu, R.H. Fang, K.C. Wang, B.T. Luk, S. Thamphiwatana, D. Dehaini, et al.,
Nanoparticle biointerfacing by platelet membrane cloaking, Nature. 526 (2015)
118–121.
[27] M. Longmire, P.L. Choyke, H. Kobayashi, Clearance properties of nano-sized
particles and molecules as imaging agents: considerations and caveats,
Nanomedicine (London) 3 (2008) 703–717.
[28] S.S. Hossain, Y. Zhang, X. Liang, F. Hussain, M. Ferrari, T.J. Hughes, et al., In
silico vascular modeling for personalized nanoparticle delivery, Nanomedicine
(London) 8 (2013) 343–357.
[29] J. Tan, A. Thomas, Y. Liu, Influence of red blood cells on nanoparticle targeted
delivery in microcirculation, Soft Matter 8 (2011) 1934–1946.
[30] R. Toy, E. Hayden, C. Shoup, H. Baskaran, E. Karathanasis, The effects of particle
size, density and shape on margination of nanoparticles in microcirculation,
Nanotechnology. 22 (2011) 115101.
[31] F. Gentile, C. Chiappini, D. Fine, R.C. Bhavane, M.S. Peluccio, M.M. Cheng, et al.,
The effect of shape on the margination dynamics of non-neutrally buoyant
particles in two-dimensional shear flows, J. Biomech. 41 (2008) 2312–2318.
[32] T. Dvir, M. Bauer, A. Schroeder, J.H. Tsui, D.G. Anderson, R. Langer, et al.,
Nanoparticles targeting the infarcted heart, Nano Lett. 11 (2011) 4411–4414.
[33] W. Yu, R. Liu, Y. Zhou, H. Gao, Size-tunable strategies for a tumor targeted drug
delivery system, ACS central science. 6 (2020) 100–116.
[34] Q. Hu, Q. Chen, Z. Gu, Advances in transformable drug delivery systems,
Biomaterials. 178 (2018) 546–558.
[35] I. Canton, G. Battaglia, Endocytosis at the nanoscale, Chem. Soc. Rev. 41 (2012)
2718–2739.
[36] C. Le Roy, J.L. Wrana, Clathrin- and non-clathrin-mediated endocytic regulation
of cell signalling, Nat. Rev. Mol. Cell Biol. 6 (2005) 112–126.
[37] S.A. Smith, L.I. Selby, A.P.R. Johnston, G.K. Such, The endosomal escape of
nanoparticles: toward more efficient cellular delivery, Bioconjug. Chem. 30
(2019) 263–272.
[38] F. Benyettou, R. Rezgui, F. Ravaux, T. Jaber, K. Blumer, M. Jouiad, et al.,
Synthesis of silver nanoparticles for the dual delivery of doxorubicin and
alendronate to cancer cells, J. Mater. Chem. B 3 (2015) 7237–7245.
[39] C. Liu, W. Yu, Z. Chen, J. Zhang, N. Zhang, Enhanced gene transfection efficiency
in CD13-positive vascular endothelial cells with targeted poly(lactic acid)-poly
(ethylene glycol) nanoparticles through caveolae-mediated endocytosis,
J. Control. Release 151 (2011) 162–175.
502
Journal of Controlled Release 337 (2021) 494–504
[40] Y.M. Bae, Y.I. Park, S.H. Nam, J.H. Kim, K. Lee, H.M. Kim, et al., Endocytosis,
intracellular transport, and exocytosis of lanthanide-doped upconverting
nanoparticles in single living cells, Biomaterials. 33 (2012) 9080–9086.
[41] G.K. Such, Y. Yan, A.P. Johnston, S.T. Gunawan, F. Caruso, Interfacing materials
science and biology for drug carrier design, Adv. Mater. 27 (2015) 2278–2297.
[42] M. Gunata, H. Parlakpinar, A review of myocardial ischaemia/reperfusion injury:
pathophysiology, experimental models, biomarkers, genetics and
pharmacological treatment, Cell Biochem. Funct. 39 (2) (2020) 190–217.
[43] H. Tsutsui, S. Kinugawa, S. Matsushima, Oxidative stress and heart failure, Am. J.
Physiol. Heart Circ. Physiol. 301 (2011) H2181–H2190.
[44] A. van der Pol, W.H. van Gilst, A.A. Voors, P. van der Meer, Treating oxidative
stress in heart failure: past, present and future, Eur. J. Heart Fail. 21 (2019)
425–435.
[45] M.G. Perrelli, P. Pagliaro, C. Penna, Ischemia/reperfusion injury and
cardioprotective mechanisms: role of mitochondria and reactive oxygen species,
World J. Cardiol. 3 (2011) 186–200.
[46] A.K. Jain, N.K. Mehra, N.K. Swarnakar, Role of antioxidants for the treatment of
cardiovascular diseases: challenges and opportunities, Curr. Pharm. Des. 21
(2015) 4441–4455.
[47] J.G. Farias, V.M. Molina, R.A. Carrasco, A.B. Zepeda, E. Figueroa, P. Letelier, et
al., Antioxidant therapeutic strategies for cardiovascular conditions associated
with oxidative stress, Nutrients. 9 (9) (2017) 966.
[48] O. Pechanova, E. Dayar, M. Cebova, Therapeutic potential of polyphenols-loaded
polymeric nanoparticles in cardiovascular system, Molecules. 25 (15) (2020)
3322.
[49] J. Kim, L. Cao, D. Shvartsman, E.A. Silva, D.J. Mooney, Targeted delivery of
nanoparticles to ischemic muscle for imaging and therapeutic angiogenesis, Nano
Lett. 11 (2011) 694–700.
[50] S. Taurin, H. Nehoff, K. Greish, Anticancer nanomedicine and tumor vascular
permeability; where is the missing link? J. Control. Release 164 (2012) 265–275.
[51] G.U. Ruiz-Esparza, J.H. Flores-Arredondo, V. Segura-Ibarra, G. Torre-Amione,
M. Ferrari, E. Blanco, et al., The physiology of cardiovascular disease and
innovative liposomal platforms for therapy, Int. J. Nanomedicine 8 (2013)
629–640.
[52] F. Forini, P. Canale, G. Nicolini, G. Iervasi, Mitochondria-targeted drug delivery
in cardiovascular disease: a long road to nano-cardio medicine, Pharmaceutics.
12 (11) (2020) 1122.
[53] Y. Cheng, D.Z. Liu, C.X. Zhang, H. Cui, M. Liu, B.L. Zhang, et al., Mitochondria-
targeted antioxidant delivery for precise treatment of myocardial ischemia-
reperfusion injury through a multistage continuous targeted strategy, Nanomed.
Nanotechnol. Biol. Med. 16 (2019) 236–249.
[54] N.V. Skorodumova, S.I. Simak, B.I. Lundqvist, I.A. Abrikosov, B. Johansson,
Quantum origin of the oxygen storage capability of ceria, Phys. Rev. Lett. 89
(2002) 166601.
[55] S.S. El Shaer, T.A. Salaheldin, N.M. Saied, S.M. Abdelazim, In vivo ameliorative
effect of cerium oxide nanoparticles in isoproterenol-induced cardiac toxicity,
Exp. Toxicol. Pathol. 69 (2017) 435–441.
[56] C. Kang, W. Cho, M. Park, J. Kim, S. Park, D. Shin, et al., H2O2-triggered bubble
generating antioxidant polymeric nanoparticles as ischemia/reperfusion targeted
nanotheranostics, Biomaterials. 85 (2016) 195–203.
[57] D.D. Verma, W.C. Hartner, V. Thakkar, T.S. Levchenko, V.P. Torchilin, Protective
effect of coenzyme Q10-loaded liposomes on the myocardium in rabbits with an
acute experimental myocardial infarction, Pharm. Res. 24 (2007) 2131–2137.
[58] R.S. Soumya, A. Prathapan, P.S. Raj, V.P. Vineetha, K.G. Raghu, Selenium
incorporated guar gum nanoparticles safeguard mitochondrial bioenergetics
during ischemia reperfusion injury in H9c2 cardiac cells, Int. J. Biol. Macromol.
107 (2018) 254–260.
[59] B. Cote, L.J. Carlson, D.A. Rao, A.W.G. Alani, Combinatorial resveratrol and
quercetin polymeric micelles mitigate doxorubicin induced cardiotoxicity in vitro
and in vivo, J. Control. Release 213 (2015) 128–133.
[60] T.A. Johnson, N.A. Stasko, J.L. Matthews, W.E. Cascio, E.L. Holmuhamedov, C.
B. Johnson, et al., Reduced ischemia/reperfusion injury via glutathione-initiated
nitric oxide-releasing dendrimers, Nitric Oxide Biol. Chem. 22 (2010) 30–36.
[61] A. Ray, S. Rana, D. Banerjee, A. Mitra, R. Datta, S. Naskar, et al., Improved
bioavailability of targeted Curcumin delivery efficiently regressed cardiac
hypertrophy by modulating apoptotic load within cardiac microenvironment,
Toxicol. Appl. Pharmacol. 290 (2016) 54–65.
[62] O. Lozano, A. Lazaro-Alfaro, C. Silva-Platas, Y. Oropeza-Almazan, A. Torres-
Quintanilla, J. Bernal-Ramirez, et al., Nanoencapsulated quercetin improves
cardioprotection during hypoxia-reoxygenation injury through preservation of
mitochondrial function, Oxidative Med. Cell. Longev. 2019 (2019) 7683051.
[63] W.E.E. Nabofa, O.O. Alashe, O.T. Oyeyemi, A.F. Attah, A.A. Oyagbemi,
Omobowale TO, et al., Cardioprotective effects of curcumin-nisin based poly
lactic acid nanoparticle on myocardial infarction in guinea pigs, Sci. Rep. 8
(2018) 16649.
[64] H.M. Sanders, G.J. Strijkers, W.J. Mulder, H.P. Huinink, S.J. Erich, O.C. Adan, et
al., Morphology, binding behavior and MR-properties of paramagnetic collagen-
binding liposomes, Contrast media & molecular imaging. 4 (2009) 81–88.
[65] K.Y. DeLeon-Pennell, C.A. Meschiari, M. Jung, M.L. Lindsey, Matrix
metalloproteinases in myocardial infarction and heart failure, Prog. Mol. Biol.
Transl. Sci. 147 (2017) 75–100.
[66] R. Schmidt, A. Bultmann, M. Ungerer, N. Joghetaei, O. Bulbul, S. Thieme, et al.,
Extracellular matrix metalloproteinase inducer regulates matrix
metalloproteinase activity in cardiovascular cells: implications in acute
myocardial infarction, Circulation. 113 (2006) 834–841.
C. Lin et al.
[67] A. Ducharme, S. Frantz, M. Aikawa, E. Rabkin, M. Lindsey, L.E. Rohde, et al.,
Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular
enlargement and collagen accumulation after experimental myocardial
infarction, J. Clin. Invest. 106 (2000) 55–62.
[68] Z. Fan, M. Fu, Z. Xu, B. Zhang, Z. Li, H. Li, et al., Sustained release of a peptide-
based matrix metalloproteinase-2 inhibitor to attenuate adverse cardiac
remodeling and improve cardiac function following myocardial infarction,
Biomacromolecules. 18 (2017) 2820–2829.
[69] A. Krzywonos-Zawadzka, A. Franczak, A. Olejnik, M. Radomski, J.F. Gilmer,
G. Sawicki, et al., Cardioprotective effect of MMP-2-inhibitor-NO-donor hybrid
against ischaemia/reperfusion injury, J. Cell. Mol. Med. 23 (2019) 2836–2848.
[70] I. Cuadrado, M.J. Piedras, I. Herruzo, C. Turpin Mdel, B. Castejon, P. Reventun, et
al., EMMPRIN-targeted magnetic nanoparticles for in vivo visualization and
regression of acute myocardial infarction, Theranostics. 6 (2016) 545–557.
[71] M.M. Nguyen, A.S. Carlini, M.P. Chien, S. Sonnenberg, C. Luo, R.L. Braden, et al.,
Enzyme-responsive nanoparticles for targeted accumulation and prolonged
retention in heart tissue after myocardial infarction, Adv. Mater. 27 (2015)
5547–5552.
[72] C. Fan, J. Shi, Y. Zhuang, L. Zhang, L. Huang, W. Yang, et al., Myocardial-
infarction-responsive smart hydrogels targeting matrix metalloproteinase for on-
demand growth factor delivery, Adv. Mater. 31 (2019), e1902900.
[73] T. Kalogeris, C.P. Baines, M. Krenz, R.J. Korthuis, Cell biology of ischemia/
reperfusion injury, Int. Rev. Cell Mol. Biol. 298 (2012) 229–317.
[74] R.L. Winslow, J. Rice, S. Jafri, E. Marban, B. O’Rourke, Mechanisms of altered
excitation-contraction coupling in canine tachycardia-induced heart failure, II:
model studies, Circ. Res. 84 (1999) 571–586.
[75] T.J. Samuel, R.P. Rosenberry, S. Lee, Z. Pan, Correcting calcium dysregulation in
chronic heart failure using SERCA2a gene therapy, Int. J. Mol. Sci. 19 (4) (2018)
1086.
[76] P.A. Gorski, D.K. Ceholski, R.J. Hajjar, Altered myocardial calcium cycling and
energetics in heart failure–a rational approach for disease treatment, Cell Metab.
21 (2015) 183–194.
[77] H.M. Viola, W.A. Macdonald, H. Tang, L.C. Hool, The L-type Ca(2+) channel as a
therapeutic target in heart disease, Curr. Med. Chem. 16 (2009) 3341–3358.
[78] E.L. Barle, M. Cerne, L. Peternel, M. Homar, Reduced intravenous toxicity of
amiodarone nanosuspension in mice and rats, Drug Chem. Toxicol. 36 (2013)
263–269.
[79] H. Takahama, H. Shigematsu, T. Asai, T. Matsuzaki, S. Sanada, H.Y. Fu, et al.,
Liposomal amiodarone augments anti-arrhythmic effects and reduces
hemodynamic adverse effects in an ischemia/reperfusion rat model, Cardiovasc.
Drugs Ther. 27 (2013) 125–132.
[80] S.R. Abulateefeh, M.O. Taha, Enhanced drug encapsulation and extended release
profiles of calcium-alginate nanoparticles by using tannic acid as a bridging cross-
linking agent, J. Microencapsul. 32 (2015) 96–105.
[81] K. Manjunath, V. Venkateswarlu, A. Hussain, Preparation and characterization of
nitrendipine solid lipid nanoparticles, Die Pharmazie. 66 (2011) 178–186.
[82] M.D. Freedman, J.C. Somberg, Pharmacology and pharmacokinetics of
amiodarone, J. Clin. Pharmacol. 31 (1991) 1061–1069.
[83] L. Nagy, A. Kovacs, B. Bodi, E.T. Pasztor, G.A. Fulop, A. Toth, et al., The novel
cardiac myosin activator omecamtiv mecarbil increases the calcium sensitivity of
force production in isolated cardiomyocytes and skeletal muscle fibres of the rat,
Br. J. Pharmacol. 172 (2015) 4506–4518.
[84] N. Kiaie, S.H. Emami, S. Rabbani, R.M. Aghdam, H.A. Tafti, Targeted and
controlled drug delivery to a rat model of heart failure through a magnetic
nanocomposite, Ann. Biomed. Eng. 48 (2020) 709–721.
[85] A. Florian, A. Ludwig, S. Rosch, H. Yildiz, S. Klumpp, U. Sechtem, et al., Positive
effect of intravenous iron-oxide administration on left ventricular remodelling in
patients with acute ST-elevation myocardial infarction - a cardiovascular
magnetic resonance (CMR) study, Int. J. Cardiol. 173 (2014) 184–189.
[86] W.D. Gray, P. Che, M. Brown, X. Ning, N. Murthy, M.E. Davis, N-
acetylglucosamine conjugated to nanoparticles enhances myocyte uptake and
improves delivery of a small molecule p38 inhibitor for post-infarct healing,
J. Cardiovasc. Transl. Res. 4 (2011) 631–643.
[87] S.A. Marsh, H.E. Collins, J.C. Chatham, Protein O-GlcNAcylation and
cardiovascular (patho)physiology, J. Biol. Chem. 289 (2014) 34449–34456.
[88] J.T. Maxwell, I. Somasuntharam, W.D. Gray, M. Shen, J.M. Singer, B. Wang, et al.,
Bioactive nanoparticles improve calcium handling in failing cardiac myocytes,
Nanomedicine (London) 10 (2015) 3343–3357.
[89] P. Most, J. Bernotat, P. Ehlermann, S.T. Pleger, M. Reppel, M. Borries, et al.,
S100A1: a regulator of myocardial contractility, Proc. Natl. Acad. Sci. U. S. A. 98
(2001) 13889–13894.
[90] K. Manjunath, V. Venkateswarlu, Pharmacokinetics, tissue distribution and
bioavailability of nitrendipine solid lipid nanoparticles after intravenous and
intraduodenal administration, J. Drug Target. 14 (2006) 632–645.
[91] G. Ikeda, T. Matoba, Y. Nakano, K. Nagaoka, A. Ishikita, K. Nakano, et al.,
Nanoparticle-mediated targeting of cyclosporine a enhances cardioprotection
against ischemia-reperfusion injury through inhibition of mitochondrial
permeability transition pore opening, Sci. Rep. 6 (2016) 20467.
[92] N. Hardy, H.M. Viola, V.P. Johnstone, T.D. Clemons, H. Cserne Szappanos,
R. Singh, et al., Nanoparticle-mediated dual delivery of an antioxidant and a
peptide against the L-type Ca2+ channel enables simultaneous reduction of
cardiac ischemia-reperfusion injury, ACS Nano 9 (2015) 279–289.
[93] S.C. Latet, V.Y. Hoymans, P.L. Van Herck, C.J. Vrints, The cellular immune system
in the post-myocardial infarction repair process, Int. J. Cardiol. 179 (2015)
240–247.
503
Journal of Controlled Release 337 (2021) 494–504
[94] M. Horckmans, L. Ring, J. Duchene, D. Santovito, M.J. Schloss, M. Drechsler, et
al., Neutrophils orchestrate post-myocardial infarction healing by polarizing
macrophages towards a reparative phenotype, Eur. Heart J. 38 (2017) 187–197.
[95] A. Mantovani, A. Sica, S. Sozzani, P. Allavena, A. Vecchi, M. Locati, The
chemokine system in diverse forms of macrophage activation and polarization,
Trends Immunol. 25 (2004) 677–686.
[96] P.C. Westman, M.J. Lipinski, D. Luger, R. Waksman, R.O. Bonow, E. Wu, et al.,
Inflammation as a driver of adverse left ventricular remodeling after acute
myocardial infarction, J. Am. Coll. Cardiol. 67 (2016) 2050–2060.
[97] Y.J. Huang, K.C. Hung, H.S. Hung, S.H. Hsu, Modulation of macrophage
phenotype by biodegradable polyurethane nanoparticles: possible relation
between macrophage polarization and immune response of nanoparticles, ACS
Appl. Mater. Interfaces 10 (2018) 19436–19448.
[98] T. Harel-Adar, T. Ben Mordechai, Y. Amsalem, M.S. Feinberg, J. Leor, S. Cohen,
Modulation of cardiac macrophages by phosphatidylserine-presenting liposomes
improves infarct repair, Proc. Natl. Acad. Sci. U. S. A. 108 (2011) 1827–1832.
[99] I. Somasuntharam, K. Yehl, S.L. Carroll, J.T. Maxwell, M.D. Martinez, P.L. Che, et
al., Knockdown of TNF-alpha by DNAzyme gold nanoparticles as an anti-
inflammatory therapy for myocardial infarction, Biomaterials. 83 (2016) 12–22.
[100] M. Mahmoudi, I. Lynch, M.R. Ejtehadi, M.P. Monopoli, F.B. Bombelli, S. Laurent,
Protein-nanoparticle interactions: opportunities and challenges, Chem. Rev. 111
(2011) 5610–5637.
[101] M.P. Monopoli, D. Walczyk, A. Campbell, G. Elia, I. Lynch, F.B. Bombelli, et al.,
Physical-chemical aspects of protein corona: relevance to in vitro and in vivo
biological impacts of nanoparticles, J. Am. Chem. Soc. 133 (2011) 2525–2534.
[102] R. Cai, C. Chen, The crown and the scepter: roles of the protein corona in
nanomedicine, Adv. Mater. 31 (2019), e1805740.
[103] W. Xiao, H. Gao, The impact of protein corona on the behavior and targeting
capability of nanoparticle-based delivery system, Int. J. Pharm. 552 (2018)
328–339.
[104] N. Bertrand, P. Grenier, M. Mahmoudi, E.M. Lima, E.A. Appel, F. Dormont, et al.,
Mechanistic understanding of in vivo protein corona formation on polymeric
nanoparticles and impact on pharmacokinetics, Nat. Commun. 8 (2017) 777.
[105] M.P. Monopoli, C. Aberg, A. Salvati, K.A. Dawson, Biomolecular coronas provide
the biological identity of nanosized materials, Nat. Nanotechnol. 7 (2012)
779–786.
[106] V. Mirshafiee, M. Mahmoudi, K. Lou, J. Cheng, M.L. Kraft, Protein corona
significantly reduces active targeting yield, Chem. Commun. 49 (2013)
2557–2559.
[107] A. Salvati, A.S. Pitek, M.P. Monopoli, K. Prapainop, F.B. Bombelli, D.R. Hristov, et
al., Transferrin-functionalized nanoparticles lose their targeting capabilities when
a biomolecule corona adsorbs on the surface, Nat. Nanotechnol. 8 (2013)
137–143.
[108] D.F. Moyano, K. Saha, G. Prakash, B. Yan, H. Kong, M. Yazdani, et al., Fabrication
of corona-free nanoparticles with tunable hydrophobicity, ACS Nano 8 (2014)
6748–6755.
[109] B.L. Oliveira, Z. Guo, G.J.L. Bernardes, Inverse electron demand Diels-Alder
reactions in chemical biology, Chem. Soc. Rev. 46 (2017) 4895–4950.
[110] N.K. Devaraj, The future of bioorthogonal chemistry, ACS central science. 4
(2018) 952–959.
[111] E.J.L. Steen, P.E. Edem, K. Norregaard, J.T. Jorgensen, V. Shalgunov, A. Kjaer, et
al., Pretargeting in nuclear imaging and radionuclide therapy: improving efficacy
of theranostics and nanomedicines, Biomaterials. 179 (2018) 209–245.
[112] K. Westerlund, A. Vorobyeva, B. Mitran, A. Orlova, V. Tolmachev, A.E. Karlstrom,
et al., Site-specific conjugation of recognition tags to trastuzumab for peptide
nucleic acid-mediated radionuclide HER2 pretargeting, Biomaterials. 203 (2019)
73–85.
[113] S.J. Dixon, K.M. Lemberg, M.R. Lamprecht, R. Skouta, E.M. Zaitsev, C.E. Gleason,
et al., Ferroptosis: an iron-dependent form of nonapoptotic cell death, Cell. 149
(2012) 1060–1072.
[114] W.S. Yang, B.R. Stockwell, Ferroptosis: death by lipid peroxidation, Trends Cell
Biol. 26 (2016) 165–176.
[115] Y. Xie, W. Hou, X. Song, Y. Yu, J. Huang, X. Sun, et al., Ferroptosis: process and
function, Cell Death Differ. 23 (2016) 369–379.
[116] S.J. Dixon, B.R. Stockwell, The role of iron and reactive oxygen species in cell
death, Nat. Chem. Biol. 10 (2014) 9–17.
[117] H. Bulluck, S. Rosmini, A. Abdel-Gadir, S.K. White, A.N. Bhuva, T.A. Treibel, et
al., Residual myocardial iron following intramyocardial hemorrhage during the
convalescent phase of reperfused ST-segment-elevation myocardial infarction and
adverse left ventricular remodeling, Circulation cardiovascular imaging. 9 (10)
(2016), e004940.
[118] W.G. Kreyling, A.M. Abdelmonem, Z. Ali, F. Alves, M. Geiser, N. Haberl, et al., In
vivo integrity of polymer-coated gold nanoparticles, Nat. Nanotechnol. 10 (2015)
619–623.
[119] B. Pelaz, C. Alexiou, R.A. Alvarez-Puebla, F. Alves, A.M. Andrews, S. Ashraf, et al.,
Diverse applications of nanomedicine, ACS Nano 11 (2017) 2313–2381.
[120] M. Malki, S. Fleischer, A. Shapira, T. Dvir, Gold Nanorod-based engineered
cardiac patch for suture-free engraftment by near IR, Nano Lett. 18 (2018)
4069–4073.
C. Lin et al.
[121] S.W. Lee, N. Yabuuchi, B.M. Gallant, S. Chen, B.S. Kim, P.T. Hammond, et al.,
High-power lithium batteries from functionalized carbon-nanotube electrodes,
Nat. Nanotechnol. 5 (2010) 531–537.
[122] S.G. Surya, S.M. Majhi, D.K. Agarwal, A.A. Lahcen, S. Yuvaraja, K.N. Chappanda,
et al., A label-free aptasensor FET based on au nanoparticle decorated Co3O4
504
Journal of Controlled Release 337 (2021) 494–504
nanorods and a SWCNT layer for detection of cardiac troponin T protein, J. Mater.
Chem. B 8 (2020) 18–26.
[123] M. Adeel, M.M. Rahman, J.J. Lee, Label-free aptasensor for the detection of
cardiac biomarker myoglobin based on gold nanoparticles decorated boron
nitride nanosheets, Biosens. Bioelectron. 126 (2019) 143–150.