Biomedicine & Pharmacotherapy 134 (2021) 111103

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Biomedicine & Pharmacotherapy

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

Review

Nanomedicines: Redefining traditional medicine

Weijia Lu a, 1, Jing Yao b, 1, Xiao Zhu a, c, d, e, *, Yi Qi a, c, d, e, *
a
Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang), Zhanjiang 524023, China
b
First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
c
Guangdong Key Laboratory for Research and Development of Natural Drugs, The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang
524023, China
d
The Key Lab of Zhanjiang for R&D Marine Microbial Resources in the Beibu Gulf Rim, Guangdong Medical University, Zhanjiang 524023, China
e
The Marine Biomedical Research Institute of Guangdong Zhanjiang, Zhanjiang 524023, China

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

Keywords: Nanomedicines offer nanoscale drug delivery system. They offer ways of promising drug transportation, and
Cancer address the issues of lack of targeting and permeability of traditional drugs. The physical and chemical properties
Nanoparticles in the domain of nanomedicine applications in vivo have not been sufficiently delivered. What’s more, the
Nanotechnology
metabolic of nanomedicines is not clear enough. Those factors which mentioned above determine that many
Targeting therapy
Review
nanomedicines have not yet realized clinical application due to their safety problems and in vivo efficacy. For
example, they may cause immune response and cytotoxicity, as well as the ability to clear organs in vivo, the
penetration ability of them and the lack of targeting ability may also cause poor efficacy of drugs in vivo. In this
review, the new progresses of different kinds of nanomedicines (including gold nanoparticles, nanorobots, black
phosphorus nanoparticles, brain diseases, gene editing and immunotherapy etc.) in anti-tumor, antibacterial,
ocular diseases and arteriosclerosis in recent years were summarized. Their shortcomings were pointed out, and
the new methods to improve the biosafety and efficacy were summarized.

1. Introduction Traditional small molecule drugs have no special selectivity, and

The field of nanomedicine is the science and technology of diag­
nosing, treating and preventing disease and traumatic injury, of
relieving pain, and of preserving and improving human health, using
molecular tools and molecular knowledge of the human body. Nano­
medicines can be endowed with characteristics different from tradi­
tional drugs by embedding drugs in carriers or modifying nanodrugs [1,
2].
they need to pay attention to the dosage and frequency, and can lead to
serious side effects. They do not pass through some biological barriers,
and their efficacy may also affect due to the poor solubility. In contrast,
nanomedicines are targeted and help to reduce drug toxicity and
improve bioavailability. It can slow-release drugs and prolong the half-
life of them. More importantly, the solubility and permeability of
insoluble drugs should be improved to make the drugs cross biological
barriers [3]. It is primarily used in disease diagnosis, treatment,

Abbreviations: AIDS, acquired immune deficiency syndrome; AuNFs, gold nanoframeworks; BBB, blood-brain barrier; BP, black phosphorus; BPNS, black phos­
phorus nanosheets; BTZ, bortezomib; BV, biliverdin; CNV, choroidal neovascularization; CO, carbon monoxide; CPT, camptothecin; CRISPR, clustered regularly
interspaced short palindromic repeats; CuS, copper sulfide; DCs, dendritic cells; DDS, drug delivery system; EGFR, epidermal growth factor receptor; EPR effect,
enhanced permeability and retention effect; GSH, glutathione; H2, hydrogen; H2S, hydrogen sulfide; HIV, human immunodeficiency virus; ICD, immunogenic cell
death; IDO1, indoleamine 23-dioxygenase 1; IgM, immunoglobulin M; MFIONs, magnetosome-like ferrimagnetic iron oxide nanochains; MNPs, magnetic nano­
particles; MSCs, mesenchymal stem cells; MTOR, rapamycin; NaCl, sodium chloride; NICS, nano immunoconjugates; NIR, near-infrared; NIR-II, the second near-
infrared; NO, nitric oxide; NPs, nanoparticles; PACT, photoacoustic computed tomography; PCE, photothermal conversion efficiency; PD, Parkinson’s disease; PDT,
photodynamic therapy; PEG, polyethylene glycol; PMLA, poly(β-L-malic acid); PTT, photothermal therapy; ROS, reactive oxygenspecies; SIRT1, silent information
regulator; SnTe, tin telluride; STING, stimulator of interferon genes; TDLNs, tumor-draininglymph nodes; tFNA, tetrahedral framework nucleic acid; WAT, white
adipose tissue.
* Corresponding authors at: Guangdong Key Laboratory for Research and Development of Natural Drugs, The Marine Biomedical Research Institute, Guangdong
Medical University, Zhanjiang 524023, China.
E-mail addresses: xzhu@gdmu.edu.cn (X. Zhu), qiyi7272@gdmu.edu.cn (Y. Qi).
1
These authors have contributed equally to this work.

https://doi.org/10.1016/j.biopha.2020.111103
Received 21 October 2020; Received in revised form 24 November 2020; Accepted 1 December 2020
Available online 15 December 2020
0753-3322/© 2020 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
W. Lu et al.
monitoring and other drugs or biological products to improve human
health [4,5]. In recent years, nanomedicine has great development po­
tential and application prospect in clinical treatment of the tumor. In
addition to tumor treatment, nanomedicine can also be used in
anti-infection, ophthalmic disease, neurological disease, gene editing,
immunotherapy and so on. Although nanotechnology has been proposed
for decades [6], because of the great changes in physical and chemical
properties of nanomaterials, the physicochemical properties and meta­
bolic pathways of nanotechnology still need to be studied [7].
There is now broad consensus among medical researchers and
practitioners that along with personalized medicine and regenerative
medicine, nanomedicine is likely to revolutionize our definitions of what
constitutes human disease and its treatment. At present, research on
intelligent nanorobots is also very popular. The rise of artificial intelli­
gence (AI) also brings hope for the clinical transformation of nano­
medicines [8]. In light of these developments, incorporation of key
nanomedicine concepts into the general medical curriculum ought to be
considered. Although there have been a lot of reports on nanomedicines
which focus on the developments of new carriers rather than clinical
transformation. The purpose of this paper is to review the main progress
of nanomedicine and its application in different therapeutic strategies,
and to make a prospect for its future development [9].
2. The main types and research progress of nanomedicines
Nanomedicines include inorganic nanomaterials (metal & metal
oxide nanoparticles, carbon nanotubes, black phosphorus nano­
particles), dendrimers, polymers, micelles, liposomes, nanocrystals, etc.
Here are some of the more important nanomedicines and their research
progress.
2.1. Nanocrystals
Nanocrystals are colloidal dispersive systems mainly formed by
drugs, which can be stabilized and dispersed by modification of a small
amount of surfactant or polymer materials [10]. They have high drug
loading capacity, which approach 100 %. They can improve the solu­
bility and bioavailability of the drugs without carrier materials [11,12].
2.2. Liposomes
Due to the modifiable sites, liposome nanodrugs have excellent
biocompatibility and dependability, which can achieve targeting,
improve the water solubility, slow-release drugs, and can also be made
into vaccine carriers [13]. So far, they are most variety of nanomedicines
on the market. The in vivo stability of mesoporous silica nanoparticles
can be improved by encapsulating them with liposomes [14]. Never­
theless, although the manufacturing process can also reduce their
curative effect, liposomes may cause drug leakage when conditions such
as the pH or temperature change [15]. Liposome hydrogel can improve
the stability of the liposome nanodrug. The temperature can affect the
diffusion efficiency of liposomes in biological hydrogels. Preparation of
liposome nanodrugs with different phase transition temperature (Tm)
helps the treatment of diseases with different diffusion requirements
[16].
It has been reported that liposome drugs attracted Immunoglobulin
M (IgM) in vivo and induce immunogenicity, and the protein corona of
plasma protein formation also affected their targeting [17]. Using the
apolipoprotein in the plasma as a target factor does not cause immu­
nogenicity, and can be utilized to cross the blood-brain barrier (BBB)
[18].
2.3. Black phosphorus (BP)
Carbon nanotubes have recently been added to the SIN (‘Substitute It
Now’) list to their carcinogenicity and reproductive toxicity [19].
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Biomedicine & Pharmacotherapy 134 (2021) 111103
However, black phosphorus nanosheets (BPNS) can be used as their new
substitution of high drug loading, which has better biocompatibility and
rapid degradation [20,21]. The organic combination of BPNS with Cu2 +
can enhance their photothermal effect and make them possess excellent
rapid degradation and photothermal stability, which are not available in
traditional phototherapeutic materials [22].
In recent years, it has become a research hotspot to study the com­
bination of multiple models and new nanomaterials for the treatment of
tumors. BPNS realize the combination of chemotherapy and photo­
thermal therapy for the treatment of pulmonary metastatic tumors [23].
The combination of photothermal therapy and photodynamic therapy is
also realized, which improves the stability of the drug [20]. In addition
to cancer applications, the newly prepared black phosphorus (BP) drugs
can also be used to assist in the treatment of depression [24]. BP has
potent biological activity and can be used as an antioxidant in
oxidation-reduction targeted therapy, which is a new field to be
explored. Hou et al. suggested that it could be effectively removed
reactive oxygen species (ROS) in the kidney and protected the kidney
from ROS damage [25].
2.4. Gold nanoparticles
Gold nanoparticles (NPs) are made of gold and are characterized by
safety. Hocevar has shown that they do not adversely affect the immune
function of B lymphocytes in vitro for the first time [26]. They could be
used as materials of photothermal therapy and for tumor treatment [27],
weight loss therapy and so on [28,29]. Recently, tumor cells have been
found to have the ability to synthesize gold nanoparticles (NPs). This
new biogenic route of gold NPs synthesis can synthesize spherical,
anisotropic and high aspect ratio gold nanomaterials [27,30]. Molecular
dynamics simulation and experimental photothermal therapy show that
these nanomaterials are proven to be excellent imaging agents and drug
carriers, improve bioavailability in vitro and in vivo, and demonstrate
good safety [31–34]. The molecular dynamic simulation and supported
with experimental photothermal therapy shown excellent application of
these nanomaterials into nanomedicine for clearing biofilm and pro­
moting the grown of fibroblast [35,36]. The gold nanoparticles loaded
with clustered regularly interspaced short palindromic repeats (CRISPR)
could be used to edit the genes of hematopoietic stem cells, promising
cures for blood diseases and acquired immune deficiency syndrome
(AIDS) [37].
However, gold nanoparticles have the problem of aggregation. The
stability of gold nanoparticles in biological samples can be enhanced and
the aggregation in vivo can be prevented by coating gold nanoparticles
with protective polymer and making them spherical or selenium- (Se-)
terminated polyethylene glycol (PEG) [26,38]. Zhang et al. has com­
bined gold nanoparticles and DNA ribbon, improving the targeting
properties of simple DNA nanoassembly materials. It is expected to be
used as a new carrier for tumor targeting drug delivery [39].
2.5. Polymeric nanomedicines
Polymeric/polymer nanoparticles is a material composed of poly­
mer, combining metal particles, inorganic nonmetal particles or organic
matter at the nanoscale [40]. They could be utilized to treat neurological
diseases and improve the drug delivery of the brain, extending the drug
blood circulation time and improving the material utilization. Chen
et al. developed a newly nanomedrug for Parkinson’s disease, opening
up an oral approach that can cross the gastrointestinal and blood-brain
barriers [41]. A novel polymer can reduce the off-target toxicity of
chemotherapy coupled with photodynamic therapy [42].
The polymeric nanomedicine synthesized by mimicking the viral
structure can control drug release, and assist macromolecular drugs to
break away from vesicles and avoid being degraded by lysosomes [43].
W. Lu et al.
2.6. Medical nanorobots
2.6.1. Functions of medical nanorobots
Nanorobots refer to the size of nanoscale robot, which can accurately
build and manipulate objects on the nanoscale. Their advantages lie in
their targeting and controllable movement, which contributes the ability
of drugs to cross biological barriers [44,45]. At present, there are
numerous researches on the treatment of tumors. For example, Wu et.al
used photoacoustic computed tomography (PACT) to realize real-time
imaging and control the nanorobots tract [46].
2.6.2. Classification of medical nanorobots
Nanorobots can be divided into two types: outfield drive and self-
drive. The driving force of outfield drives generally comes from
outfield, such as an optical drive, the sound field drive, magnetic field
drive and so on [47,48]. Self-drive nanorobots can obtain power from
the fluid environment through chemical reactions or enzymes [49]. In
recent years, the research on biological hybrid nanobots that use biology
to promote nanobots has also increased [50].
2.6.2.1. Magnetic nanorobots. The nanomedicines driven by the mag­
netic field were called magnetic nanorobots, or magnetic nanoparticles
(MNPs). One of the advantages of magnetic nanorobots is that they can
enhance the penetration of drugs in solid tumors. However, it only re­
flected in superficial tumors in the past. In recent years, some new
progress has been made in further deepening the permeability of mag­
netic nanoparticles. Liu developed a system of two oppositely polarized
external magnets could increase the drug permeability in solid tumors
by five times [51]. A nanospinners made of magnetic nanoparticles
could also enhance the penetration depth of drugs by applying me­
chanical force to the rotating magnetic field and targeting the mito­
chondria of deep cancer cells [52]. Zhou et al. used a two-magnet
configuration to introduce a constant magnetic field gradient, which
greatly enhances the accumulation and penetration of MNPs in solid
tumor models [53].
It is a research hotspot to make magnetic nanorobots overcome the
complex structure of the human body to reach specific sites. In 2019,
Huang et al. developed a magnetic nanorobot that can change its shape
according to pass through narrow, curved blood vessels. It can move
freely in the body with the fluid flows, depending on changes in the
surrounding electric field [54]. In the same year, Zhong et al. developed
a new drug to study the nucleus of tumor cells by using optical tweezers,
without destroying the cell membrane or cytoskeleton. It can use to
study the characteristics of cancer cells, and may point out the direction
for strengthening diagnosis and treatment [55].
In order to make the magnetic nanorobots effective, it is necessary to
monitor their track [56]. Yan et al. replaced fluorescence based imaging
with MR imaging, which has a stronger ability to penetrate tissues [57].
The nanorobots can be precisely concentrated in a small area of the
retina, by using clinical optical coherence tomography [58]. Currently,
some magnetic nanoparticles have begun to be used for in vitro diag­
nosis and treatment, but there is still a long way to go before they are
widely used for in vivo diagnosis and treatment due to the limited
cytotoxicity of nanomaterials [4].
2.6.2.2. DNA nanorobots. DNA can connect other molecules with its
negative potential phosphate groups after damaging the highly struc­
tured water surface on its surface, which plays an important role in its
stability [59]. DNA origami can be used for self-assembly of nano­
particles or as a vehicle to guide drug delivery. The former reduces
immunogenicity by assembling new systems from the bottom-up to
reduce the size of nanomedicines [60]. The latter can achieve voluntary
movement to the target in vivo by connecting the aptamers [61]. Their
activities are actually triggered by environmental stimuli (such as pH or
temperature) or by chemicals (such as DNA strands, small molecules,
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Biomedicine & Pharmacotherapy 134 (2021) 111103
antibodies) [62,63]. In 2018, Li et al. developed an independent DNA
nanorobot system, which can recognize tumor-associated endothelial
cells, induced tumor vascular embolism. Thus the tumor blood supply
was blocked without affecting the vascular system in healthy tissues
[64] (Fig. 1).
However, aptamers are also unstable. To solve this problem, Ma et al.
increased the biological stability and anticancer activity of aptamer by
adding tetrahedral framework nucleic acid (tFNA) to the anti-HER2
aptamer [65].
2.6.2.3. Micro/nanomachines based on biological cells. Connected with
cells or bacteria and other organisms, micro/nanomachines based on
biological cells are endowed with autonomous movement ability [50,
66]. There are built by coupling the motile microorganism (responsible
for movement) with the synthetic structure (providing other functions)
[67]. Cells used to build their units include bacteria, sperm cells, heart
muscle cells, and white blood cells [68,69]. These nanorobots enable the
active and targeted delivery of drugs in vivo, avoiding over-dependence
on EPR effects, and can simultaneously possess biological characteris­
tics. For example, microalgae tend to light, while biological cells such as
sperm and bacteria have an intrinsic system for responding to hypoxia
stimuli, as well as a directional environment (temperature, magnetic
field, pH, glucose) [66].
The latest trend of research on biological hybrid nanorobots focuses
on their application in precision medicine for clinical transition, such as
how to reduce the size of nanorobots [45,70].
2.7. Polymeric micelles
Polymeric micelles have core-shell structure, which can encapsulate
hydrophobic drugs, provide modification points and reduce drug
toxicity [71]. Micellar docetaxel regulates tumor immune microenvi­
ronment and increases the proportion between M1 and M2-like mac­
rophages, which can be used in combination chemotherapy and
immunotherapy [72]. It should not be ignored that photodynamic
therapy combined with chemotherapy is toxic, and a polymeric micelle
can control drug release and reduce off-target toxicity [42]. Li et al.
found that the synergistic effect of cisplatin crosslinking and polymeric
prodrug could be used to prepare polymer prodrug micelle in order to
further improve its retention time in blood circulation [3].
3. Advances in the application of nanomedicines in different
fields
3.1. Applications of nanomedicines in cancer
The dense tumor tissues make it difficult for traditional drugs to
penetrate. However, nanomedicine can increase drug penetration, pro­
longing circulation time, and reduce the accumulation of drugs in non-
target tissues, thus having unique advantages in the treatment of tumors.
The vascular endothelial cell gap of the tumor is large, so nanomedicine
can enter into the tumor tissue through the vascular endothelial cell gap
and enrich, which is called enhanced permeability and retention effect
(EPR effect) of the tumor [73]. Mitochondria of tumor cells can be used
as targets for nanomedicine because they produce ROS [20,74].
Increasing the osmotic and promoting cell lysis through nanoparticles
containing sodium chloride (NaCl) nanoparticles is also a new way to
kill tumors [75]. In addition, Wang et al. proposed the development of
nano-gas drugs (that is the gas-releasing nanomedicines), which can be
used to release hydrogen (H2), carbon monoxide (CO), nitric oxide (NO),
and hydrogen sulfide (H2S) to inhibit mitochondrial respiration of tumor
cells, so as to treat cancer and other diseases [76].
3.1.1. Immunotherapy of tumor with nanomedicines
Targeting the mechanism of tumor immune escape, tumor
W. Lu et al. Biomedicine & Pharmacotherapy 134 (2021) 111103

Fig. 1. DNA nanorobots block tumor blood vessels.

DNA nanobots loaded thrombins recognize the nuclear protein and change their shape, releasing thrombins to cause the tumor blood vessel obstruction. Thus the
tumor is a lack of nutrition.

immunotherapy can control and kill tumor cells by activating and Therefore, it is necessary to improve PTT or develop novel nano­
strengthening the immune system, or by cutting off the inhibitory im­ materials with clear metabolism and good bio-safety, better photo­
mune regulation of the immune checkpoint with checkpoint inhibitors stability, and high PCE [85,86].
[77]. Nevertheless, the efficacy of immunotherapy has individual dif­ Endogenous materials have the advantage of having a clear meta­
ferences, which is usually merely used as an adjuvant therapy combined bolic mechanism. Biliverdin (BV), the recently developed near-infrared
with surgery, chemotherapy, radiotherapy, and so on [78]. (NIR) absorption pigment, has no obvious toxic and side effects [85].
A mounting number of studies have been conducted on the appli­ The development of nanomaterials with high absorption capacity in the
cation of nanomedicine in combination with immunotherapy. The ad­ second near-infrared (NIR-II) is helpful to improve the photothermal
vantages are as follows: first, the synergistic effect of multiple therapies therapy of deep tumors. The newly developed materials include new
can make up for the deficiencies and avoiding tumor metastasis, such as gold nanoframeworks (AuNFs), the Gd- and copper sulfide (CuS)-inte­
improving the application rate of tumor immune drugs in different pa­ grated nanogel [87,88]. The nanomedicine developed by Zhang et al.
tients [79,80]. Second, the delivery capacity is strong enough to carry a was wrapped with MnO2 and soybean phospholipid, which has high PCE
variety of immune checkpoint inhibitors. Third, anti-cancer immunity (NIR-I is 38.2 %, NIR-II is 43.9 %). It is also mediated by NIR-II mediated
can be reinforced by inducing immunogenic cell death (ICD) [75]. The and has good biodegradability [89].
indoleamine 2,3-dioxygenase 1 (IDO1) siRNA was delivered to In the aspect of improving PCE, there are also some new nanodrugs.
tumor-draining lymph nodes (TDLNs) and tumor tissues simultaneously For example, NIR - absorbing quaterrylenediimide chromophore has
by cationic lipid-assisted nanoparticles, which could interfere with the high stability and high photothermal conversion efficiency (PCE) [90].
IDO1 pathway and enhance the immune response induced by ICD [81]. In addition, a nanomedicine that can be degraded by enzymes in vivo
The tumor microenvironment can affect the effect of immuno­ has the PCE compared with the other PTT agents previously reported
therapy. The delivery of NO to the tumor by nanosystem can improve [84] (Table 1). Generally speaking, the PCE of polymer nanoparticles is
the tumor microenvironment. However, it used to rely too much on
external excitation, but current research shows that nanomedicines
combine radioisotope to stimulate the continuous release of NO by Table 1
endogenous light, which can help activate the immune system to elim­ Comparison of photothermal conversion efficiency of various photothermal
inate metastatic tumors [82]. Semiconducting Polymer Nanoreporters agents.
can be used for immunoactivated near-infrared chemiluminescence Usage Nanoparticles PCE References
imaging during cancer immunotherapy. It can sensitively distinguish Tumor BP@Cu nanostructure 35.4％ Hu et al.(2020)
immune cells from other cells (including cancer and normal cells) and is [17]
used to track T cell activation [83]. Tumor Biliverdin (BV) nanoagents 34.3 % Xing et al.(2019)
[61]
Tumor water-soluble quaterrylenediimide 64.7 ± 4 % Liu et al.(2018)
3.1.2. Photothermal therapy of tumor with nanomedicines (QDI) [62]
Photothermal therapy (PTT) has the advantages of noninvasive, Tumor Gd-/CuS-Loaded Functional 26.7 % Zhang et al.(2020)
precise manipulation, and good therapeutic effect. The principle is to Nanogels [64]
make the high PCE of the material gathered near the tumor tissue. And Tumor SnTe@MnO2-SP NSs 43.9 %(NIR Zhang et al.(2019)
II) [65]
when exposed to an external light source (usually near-infrared), the
Tumor π-conjugated oligomer 82 % Li et al.(2019) [60]
local high temperature of tumor tissue is caused to kill cancer cells. At nanoparticles
present, the nanomaterials that have been studied for PPT have their
BP, black phosphorus; NIR-II, the second near-infrared; PCE, photothermal
own shortcomings and are slightly inadequate in clinical practice [84].
conversion efficiency; SnTe, tin telluride; SP, soybean phospholipid.

4
W. Lu et al.
higher than that of inorganic nanoparticles [40]. Phototherapy alone
cannot avoid tumor metastasis, thus it is often combined with other
therapies (including chemotherapy, immunotherapy, magnetic nano­
particles, etc.) [91,92].
3.1.3. Photodynamic therapy of tumor with nanomedicines
Compared with chemotherapy and radiotherapy, photodynamic
therapy (PDT) has the characteristics of non-invasive, low side effects,
and high selectivity [93]. The principle of PDT is that photosensitizer
excited by light of specific wavelength transmits energy to the sur­
rounding oxygen to produce singlet oxygen and other reactive oxygen
species (ROS), leading to tumor cell necrosis and apoptosis [94,95].
The mitochondria of tumor cells produce too much ROS and gluta­
thione, so it has become a promising direction of phototherapy to
transport anti-tumor drugs by targeting mitochondria, which can solve
the problem that exogenous light has permeability limitation [20,52,94,
96]. Beside, X-ray has better penetration than ordinary laser, which is
also a strategy for PDT of the deep tissues [55,97].
However, the disadvantage lies in the short life and limited action
range of ROS. The nanoreactor developed by Zhang et al. directly
released camptothecin (CPT) after being activated by ROS in mito­
chondria, which could solve this problem [98]. Also, photodynamic
therapy for oxygen dependence has found a solution. For example, the
oxygen production capacity of the organism can be used to solve it by
coating nanoparticles on the surface of spirulina platensis [99]. What’s
more, a semiconductor polymer NPs prodrug was synthesized, which
could realize the high-efficiency synergistic therapy of PDT and
chemotherapy in a hypoxic environment [93]. Cherenkov light can be
used as an in vivo light source for photodynamic therapy. Its low light
efficiency can be solved by combining nuclides with nanoparticles [82].
3.2. Applications of nanomedicines in ocular diseases
3.2.1. Deficiency of common drugs in the treatment of ocular diseases
Due to the existence of physical and physiological multi-layer
physiological barrier in the eyes, existing administration methods (eye
drops or intraocular injections) not only have a low utilization rate, but
also bring discomfort to patients.
3.2.2. Advances in research on the treatment of ocular diseases by
nanoscale drugs
Nanodrugs can increase the physiological activity of drugs, effec­
tively increase the retention time of drugs in the eye. They solve the high
effective concentration problem that common drugs have, and also assist
drugs to penetrate the physiological barrier of eyes [100]. Wu et al.
coated the liquid coating liquid layer on a spiral-shaped magnetic
nanorobot and made it get rid of the bondage of biological macromol­
ecules through the control of an external magnetic field, so as to break
through the blood-ocular barrier and accurately concentrate in the le­
sions of the eyes [44].
The antibacterial function and penetrating ability of nanomedicine
provides new ideas for the treatment of ocular diseases. Ye et al.
developed the AuAgCu2O-bromfenac sodium nanoparticles, which are
based on the principle of PTT, combined with the high-efficiency anti­
bacterial properties of silver nanoparticles and the advantages of copper
ions in promoting healing. It has the potential to be used for the infection
of drug-resistant bacteria in the eyes [101]. Wang et al. developed a
non-invasive treatment for Choroidal neovascularization (CNV) [102].
Intravenously, it is triggered by shining light on the eyes, avoiding the
destruction of retinal tissue caused by repeated intravitreal injections
and conventional laser treatment.
3.3. Applications of nanomedicines in infectious diseases
Nanomedicines are a feasible substitute for antibiotics. Although the
mechanism is not clear, studies have shown that it has a better effect on
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Biomedicine & Pharmacotherapy 134 (2021) 111103
antibiotic resistant-bacteria. Because of its targeting, it can reduce the
effective concentration of drugs and enhance the effectiveness of exist­
ing antibacterial drugs [103]. According to the principle of PTT, a sul­
fide (covellite) nanodots developed by Qiao et al. have a strong killing
effect on drug-resistant bacteria and can release Cu2 + which promotes
healing. It has the potential to be used in chronic, refractory wounds due
to infection [104]. What’s more, hydrothermal therapy had also been
shown to have good antibacterial properties. This technology has
developed a new antimicrobial strategy [105]. The strategy of killing
pathogenic bacteria by using reactive oxygen species produced by the
photocatalytic effect is considered to be one of the most promising
antibacterial treatments. Black phosphorous nanocrystals, which
combine silver nanoparticles, are excellent materials [106].
3.4. Applications of nanomedicines in diagnosis and treatment of obesity
and related metabolic diseases
The advantage of nanomedicines is to increase the bioavailability of
drugs to reduce the tremendous toxicity of traditional weight-loss drugs.
Nanomedicines for the treatment of obesity and related metabolic dis­
eases are mainly through early diagnosis, targeted delivery of drugs,
reducing blood lipid concentration, controlling appetite, inhibiting fat
absorption, transforming white adipose tissue (WAT) into brown-like
adipose tissue, etc [107–109].
Using gold nanoparticles can directly eliminate adipose tissue
through PTT, it can improve the appearance of uneven liposuction [29,
110] (Fig. 2). Prevention and treatment of atherosclerosis can be ach­
ieved by inhibiting macrophage cell proliferation with nanodrugs
loaded with simvastatin, thus achieving anti-inflammatory effects and
halting the progression of atherosclerosis [111]. Besides, increasing the
expression of silent information regulator 1 (SIRT1) in plaque can di­
agnose atherosclerosis and inhibit its growth [109]. Nanomedicines can
avoid the side effects of vascular restenosis and thrombosis caused by
surgery (such as stent implantation). For example, an atherosclerotic
drug, rapamycin (MTOR), could be wrapped in a modified red blood cell
membrane and injected into the blood to deliver the drug to the plaque
without surgery [12].
3.5. Applications of nanomedicines in brain diseases
Compared with traditional drugs, nanomedicines have the advantage
of crossing the blood-brain barrier. Recently, some studies have applied
it to Parkinson’s disease, ischemic stroke and so on [112]. The nano­
medicine used in brain diseases is mainly polymer. For example, Chen
et al. have developed an orally available drug for Parkinson’s disease
(PD), which can cross the gastrointestinal barrier and BBB [41]. Nano­
drugs can be used in mesenchymal stem cells (MSCs) - based therapy,
which can improve the secretion level of natural stem cells and cross the
blood-brain barrier. It can be used in the recovery treatment of ischemic
stroke [113].
Using poly (β-L-malic acid) (PMLA), as a carrier to construct immune
checkpoint inhibitors CTLA-4 and PD-1 antibody nano immunoconju­
gates (NICS) can effectively cross BBB and induce a local immune
response of gliomas. It is expected to be used in the treatment of brain
gliomas [114]. Nanodrugs used in the treatment of depression can in­
crease drug loading, improve the biocompatibility of fluoxetine. More
importantly, it can greatly speed up the treatment of depression [24].
3.6. Applications of nanomedicines in pulmonary diseases and heart
failure
For the treatment of pulmonary diseases, the major obstacle is to
make drugs through pulmonary surfactant without damaging [115]. In
the study of Tian et al., the nanomedicine showed a strong ability to
cross the pulmonary surfactant film without damaging lung structure
[116]. Additionally, a new nanomedicine offers the opportunity to
W. Lu et al.
improve the effectiveness of influenza virus vaccines. It transports
stimulator of interferon genes (STING) activator through the pulmonary
surfactant to produce a large number of immune mediators, which
significantly enhance the recruitment and differentiation of CD11b +
dendritic cells (DCs) and CD8 + T cells [117].
The use of drugs targeting the heart can improve efficacy. However,
it is easy to produce adverse reactions by intravenous or oral methods
[118–120]. Using the proximity of heart and lung, Miragoli et al.
developed a drug for heart disease with a new mode of transportation. It
enters the body by inhalation and is more efficient at transporting than
injections, and can be used to improve heart failure [121].
3.7. Applications of nanodrugs in gene therapy
In the process of gene modification with CRISPR, viruses are usually
used as drug carriers. In this way, the manufacturing process is complex,
which may lead to off-target effects and cause the immune response
[122]. Light is ideal for regulating CRISPR/Cas9 gene editing, whereas
most existing light sensors are sensitive only to ultraviolet or visible light
and are suitable for shallow tissues. Recently, the first CRISPR/Cas9
nanoscale vector that can be edited using near-infrared regulatory genes
has been developed, which can penetrate deeper tissues [123].
Replacing it with nanodrugs can solve the problems of cell damage,
high cost, long time consuming, and even overcome the off-target effect
[124]. In 2019, Shahbazi et al. used a gold nanomedicine as a CRISPR
vector for gene editing of hematopoietic stem cells and proved that there
was no toxicity. It is expected to be used for gene editing of the human
immunodeficiency virus (HIV) and hereditary blood diseases [37].
Moreover, some scientists have proposed another vector to replace the
virus. In 2019, Chen et al. designed a nanocapsule with thin glutathione
(GSH) coating. The experiment showed that the drug had a strong
gene-editing ability on cells, and had safety and targeting ability [125].
Nanorobots transfected with non-viruses have also been developed to
gene edit stem cells, further improving the autonomous transport of
drugs. For example, magnetosome-like ferromagnetic iron oxide nano­
chains (MFIONs) can be used to make genetic changes to stem cells that
can normally deliver recovery treatments for ischemic stroke [89,126,
127].
6
Biomedicine & Pharmacotherapy 134 (2021) 111103
Fig. 2. Treatment of obesity with PTT.
(A) Gold nanoparticles are injected into adipose
tissue.
(B) Irradiation of epidermis with 800 nm laser
increases the temperature of gold nanoparticles
and liquefies small volumes of fat.
(C) Adipose tissue and gold nanoparticles were
removed by a liposuction program.
4. The shortage and research progress of nanomedicines
4.1. Safety problem
The safety of nanodrugs has always been a difficult problem to solve.
Firstly, the deposition of nanoparticles and activation of macrophages
may contribute to adverse immune reactions. Secondly, nanodrugs may
accumulate in liver, spleen and other organs, and may cause cytotoxicity
[7,128]. The cause of the immune response is due to the size of nano­
medicine and the heterologous type of nanomedicines. Reducing the size
of nanomedicines via the bottom-up assembly strategy, developing
endogenous nanodrugs [60,70,85], or using cells to provide nanorobots
driving force [50], can improve their safety.
The prodrug is the drug delivery system (DDS) that can reduce the
cytotoxicity of drugs [129]. For example, the preparations of nano­
prodrug can solve the problems of poor stability and toxicity of borte­
zomib (BTZ) in vivo [130]. The efficiency of the precursor
nano-assembly can be refined by adding sulfur/ Selenium/Carbon
linkages to the drug. The circulation time of the drug is prolonged,
which is beneficial to cell uptake [131].
Improving targeting capabilities can reduce drug toxicity. Metallic
platinum compounds are commonly used in clinical chemotherapy for
tumors. However, due to the lack of tumor site selectivity, small mole­
cule platinum-based drugs lead to greater toxicity [7,128].
Receptor-mediated targeting can improve drug targeting. The DNA
nanocarriers take advantage of the good selectivity of cells expressing
high epidermal growth factor receptor (EGFR) to enhance the selectivity
of platinum drugs and reduce the systemic toxicity of platinum drugs for
chemotherapy [7,128].
Currently, AI (including machine learning) provides computing tools
that facilitate the simulation and modeling process in nanotherapeutics
[132]. For example, an AI toolbox can be combined to understand the
biophysical and chemical properties of the nanoscale interface [133].
In-silico methods could decipher the quantitative nanostructure
activity-relationship (Nano-QSAR) [134]. These tools can be used for
analyzing the toxicology of nanomedicines, and the accuracy is higher
than experimental animals [135]. This means significant savings in
money and time to predict the biosafety and efficacy [132].
4.2. Curative effect problem
The factors influencing the efficacy of nanodrugs are circulation,
W. Lu et al.
accumulation, penetration, internalization, and release. The main ones
are the body’s clearing mechanisms (kidney, liver, and immune system)
and the penetration and targeting capabilities of the nanomedicine itself
[136].
Nanomedicines can prolong their circulation time in vivo and
enhance the enrichment in the tumor site by modifying PEG. But PEG
restricts their uptake by tumor cells [137]. The probability of being
cleared by the immune system can be greatly reduced and the blood
circulation half-life can be prolonged by coating the nanoparticles with
cell membranes. In 2019, Chai et al. encapsulated nanocrystals of brain
tumor drugs with erythrocyte membrane. The nanocrystals were tar­
geted and could be cleared across the blood-brain barrier [11,12]. NPs
coated with CXCR4-overexpressing nerve stem cell membranes signifi­
cantly improved the efficacy of glibenclamide in stroke treatment,
enhanced nanoparticle penetration in the brain, and led to a new
approach to improve drug delivery efficiency in ischemic brain. The
drug is expected to be translated into clinical applications to improve the
treatment of stroke [138].
4.2.1. Targeting problem
Nanomedicines mainly increase the targeting ability in three di­
rections: cancer cells, tumor immune microenvironment, and peripheral
immune system [139]. The targeting of nanomedicines has special sig­
nificance in the treatment of cancer metastasis but also has some
shortcomings. First, drugs depend on tumor cell markers [140–143].
This restricts the practical application of drugs. Second, drugs that jam
the blood supply by targeting the tumor vascular system have the
insufficient targeting ability and high effective dose. Third, phage pep­
tide modified nanoparticles usually have the disadvantage of weak
target binding and cannot specifically target the relevant cell tissue.
Fourth, the targeting ability of nanodrugs is seriously decreased and the
biochemical and physical properties of NPs are seriously changed after
they are adsorbed by proteins in physiological fluids in vivo to form
protein coronas.
In view of the above shortcomings, tumor cells with higher enzyme
digestion activity than normal liver cells can design drugs targeting
cancer cells, which can produce tumor-targeting drugs without markers
[144–146]. The elimination of collagen in the tumor extracellular ma­
trix is beneficial to enhance the targeting of nanomedicine [147]. Using
DNA nanorobots to target tumor vascular system can improve the tar­
geting ability of nanomedicine, and transport thrombin to block tumor
blood vessels [64]. Wu et al. developed a nanoparticle carrier with
brain-targeting capability that could cross the blood-brain barrier,
avoiding the shortcomings of weak effectiveness and specificity of active
targeting of nanoparticles modified by phage display peptide surface. It
can be used for brain-targeted delivery of drugs for central nervous
system diseases [148]. Zhao et al. found that the reaction kinetics of
magnetic nanoparticles with the positive charge was faster, which may
be used to solve the problem of the poor targeting of NPs in vivo due to
the formation of protein coronas [149].
4.2.2. The trouble of permeability and diffusion ability
Although nanodrugs can be aggregated in the tumor site through the
EPR effect, most of them remain around the blood vessels and are
difficult to enter tumor cells through the circulatory system [150]. The
reason is the obstruction of tumor extracellular matrix (collagen, hyal­
uronic acid, etc.), high pressure, and low permeability in tumors [151,
152]. Measures to enhance the EPR effect [153] include degrading
collagen in the tumor matrix [118], reducing the size of nanoparticles,
or modifying functional groups on the surface to increase permeability.
Using the bionic lipoprotein system, tumor stroma can also be destroyed
by the photothermal effect [124].
In the last decades, it has been increasingly recognized that there is
large inter- and intra-individual heterogeneity in EPR-mediated tumor
targeting, explaining the heterogeneous outcomes of clinical trials in
which nanomedicine formulations have been evaluated [154].
7
Biomedicine & Pharmacotherapy 134 (2021) 111103
Therefore, the strategy of active transportation is being explored. It is
possible to greatly improve the permeability of nanodrugs by inducing
tumor cells to take active antitumor drugs. For example, Zhou et al.
make use of the role of endocytosis and transport to make the cells in the
adjacent layer, repeat endocytosis and transcytosis of nanomedicine.
This mechanism may enable the delivery of nanomedicine across cells
independent of diffusion [150]. However, nanorobots are likely to
achieve greater penetration [46]. Wu et al. are the first to achieve
controlled movement of a nanorobot in the eye, solving the problem of
eye medication that cannot cross multiple biological barriers [44].
5. Conclusion and perspectives
This paper mainly introduces the research progress of several kinds
of nanoparticles and their application in treating diseases in recent
years. Nanomedicines have made considerable progress in many fields,
especially in the treatment of cancer. Besides, it is of great significance in
some fields. For example, the substitution of antibiotics, and the
improvement of the permeability and targeting ability of nanorobots to
drugs. Their advantages lie in assisting drug targeting, reducing toxicity,
controlling drug–releasing, and enhancing drug penetration ability.
However, the safety and efficacy of nanomedicines cannot be ignored.
The permeability of nanomedicines can be improved by modifying
nanodrugs, but it is not enough to transport them by the EPR effect
[154]. In the future, nanomedicines or nanorobots combine with bio­
logical cells will focus on improving their biocompatibility and efficacy.
It will make them propelled inside the body without the need for so­
phisticated instrumentations, space, chemicals, acoustics, and magne­
tism. It is not only necessary to determine the efficacy of nanomedicines
in vitro, but also to further study the physicochemical properties and
pharmacokinetics of nanomedicine in vivo, so as to transform them into
clinical applications.
The development of nanomedicines in the future may not only
require animal experiments, but also the prediction of pharmacokinetic
and pharmacotoxicological properties via machine learning and AI
toolbox [155,133]. Nanomedicine is likely to develop into an
environment-friendly nanomedicine, which is harmless to biology and
has a good effect in vivo. This requires advances in artificial intelligence
algorithms and medical researchers’ commitment to the clinical trans­
formation of nanomedicine.
The modification of drug properties by nanomedicines offers
considerable possibilities, yet few clinical oncologists are aware of the
importance of antitumor nanodrugs. Therefore, it is necessary to
incorporate nanomedicine into the general medical curriculum, which is
conducive to promoting the rapid development of nanomedicine to
clinical application.
In addition to the further improvement of nanomedicines, the future
in terms of ethics and market of nanomedicines has a way to go. The
ethical issues raised by the safety and efficacy issues mentioned above
and the economic benefits of nanomedicines should also be assessed by
assess systems. Otherwise, global equality in access to health care could
be further undermined when nano-diagnosis and nano-treatment are
promoted. Respect for autonomy, beneficence, non-maleficence, and
justice will be major key biomedical ethics that policy makers and reg­
ulatory bodies need to carefully implement [156,157].
Authors’ contributions
WL wrote the manuscript. JY and XZ discussed and edited the
manuscript. XZ designed the concept. YQ and XZ supported the funding.
All authors read and approved the final manuscript.
Funding
This work was supported partly by National Natural Science Foun­
dation of China (81973908); Guangdong Science and Technology
W. Lu et al. Biomedicine & Pharmacotherapy 134 (2021) 111103

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