TYPE Review

PUBLISHED 27 June 2023

DOI 10.3389/fbioe.2023.1219054

The application of nanomedicine

OPEN ACCESS in clinical settings
EDITED BY
Tianlong Li,
Harbin Institute of Technology, China Qingsong Zhao 1, Nuo Cheng 2, Xuyan Sun 2, Lijun Yan 1* and
REVIEWED BY
Wenlan Li 1*
Renfeng Dong, 1
Postdoctoral Programme of Meteria Medica Institute of Harbin University of Commerce, Harbin, China,
South China Normal University, China 2
Department of Endocrinology, The Fourth Hospital of Harbin Medical University, Harbin, China
Shimin Yu,
Ocean University of China, China
Xiaolong Lu,
Nanjing University of Aeronautics and
Astronautics, China
As nanotechnology develops in the fields of mechanical engineering, electrical
*CORRESPONDENCE
engineering, information and communication, and medical care, it has shown
Lijun Yan,
[email protected] great promises. In recent years, medical nanorobots have made significant
Wenlan Li, progress in terms of the selection of materials, fabrication methods, driving
[email protected]
force sources, and clinical applications, such as nanomedicine. It involves
RECEIVED 08 May 2023 bypassing biological tissues and delivering drugs directly to lesions and target
ACCEPTED 05 June 2023
cells using nanorobots, thus increasing concentration. It has also proved useful for
PUBLISHED 27 June 2023
monitoring disease progression, complementary diagnosis, and minimally invasive
CITATION
Zhao Q, Cheng N, Sun X, Yan L and Li W
surgery. Also, we examine the development of nanomedicine and its applications
(2023), The application of nanomedicine in medicine, focusing on the use of nanomedicine in the treatment of various
in clinical settings. major diseases, including how they are generalized and how they are modified.
Front. Bioeng. Biotechnol. 11:1219054.
doi: 10.3389/fbioe.2023.1219054
The purpose of this review is to provide a summary and discussion of current
research for the future development in nanomedicine.
COPYRIGHT
© 2023 Zhao, Cheng, Sun, Yan and Li.
This is an open-access article distributed KEYWORDS
under the terms of the Creative
Commons Attribution License (CC BY). cross-disciplinary, micro-/nanorobots, nanotechnology, nanomedicine, drug delivery
The use, distribution or reproduction in
other forums is permitted, provided the
original author(s) and the copyright
owner(s) are credited and that the original
1 Introduction
publication in this journal is cited, in
accordance with accepted academic Modern medicine is studied to pursue a new interdisciplinary discipline named
practice. No use, distribution or
nanomedicine which combines nanotechnology and medicine (Zingg and Fischer, 2019;
reproduction is permitted which does not
comply with these terms. Germain et al., 2020). An application of nanotechnology in medicine is called nanomedicine,
while a pharmaceutical product containing nanotechnology is known as nanomedicines. For
example, a pharmaceutical containing a nanotechnology component, usually the actual drug
or a vehicle that delivers it. Nanomedicine is an umbrella term for nanotechnology with
medical applications, whereas “nanomedicines” are pharmaceuticals containing
nanotechnology components (Hall et al., 2012).
A lecture given by Richard Feynman in 1959 at Caltech envisaged machines and devices
made of individual atoms, now known as “bottom-up” nanotechnology (Olsman and
Goentoro, 2018). Gerd Binnig and Harold Rohrer won the Nobel Prize in Physics in
1986 for their scanning tunneling microscopy technique, which enables the picking up of
individual atoms and assembling them into the desired arrangement, thus greatly enabling
the development of a new technology. Carbon 60 was discovered by Richard Smalley, Robert
Curl, and Harold Kroto in 1995, winning the Nobel Prize in Chemistry. As a result of their
research on graphene, a two-dimensional carbon molecule made up of nanoscale atoms,
Andre Geim and Konstantin Novoselov were awarded the Nobel Prize in Physics in 2010.
United States and European regulatory agencies approved the first generation of
nanomedicines in the mid-1990s (Ferrari, 2010). A typical application of nanomedicine
is liposomes, which are nanoparticles (NPs) derived from lipid molecules, similar to the basic
structure of cell membranes. With nanomedicines, cytotoxic drugs are selectively delivered

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to focal areas using nanotechnology, increasing drug concentrations achieves controlled motion and targeted dwellings in a high velocity
in targeted areas, reducing damage to non-targeted areas, blood flow environment, providing a new idea for the precise
minimizing side effects, and achieving more therapeutic treatment of malignant tumors (Li et al., 2023). Micro-/
outcomes at a lower cost than conventional therapeutic nanorobots powered by light are mainly actuated by
modalities (Martin et al., 2020).Nanotechnology can establish photoinduced catalysis in semiconductors, and the action of
new routes of drug delivery and, through controlled release light-driven micro-/nanorobots in biological tissues can be
systems, improve the absorption and utilization of drugs and controlled by adjusting light intensity, light frequency, light area,
increase the targeting rate of drugs to a greater extent than in light duration or by enhancing photocatalytic efficiency (Wang Q.
conventional medicine. et al., 2020; Yang et al., 2021).Additionally, research on micro-/
Through the use of drug-loaded micro/nanorobots, the some nanorobots propelled by acoustics is essential, particularly the use of
drugs can be effectively tracted and penetrated into the relevant ultrasonic waves that can penetrate biological tissues with greater
tissues. Nanotechnology has opened up new possibilities for drug reliability (Díez et al., 2017; Mu et al., 2021). Wang et al. described a
delivery (Maheswari et al., 2018). In recent years, a large number of novel intracellular antigen delivery strategy using ultrasound (US)-
drug delivery systems have been developed, including liposomes propelled gold nanowires (AuNWs) nanomotors modfied with a
composed of phospholipid bilayers (Liu Y. et al., 2021). Hydrophilic model antigen (ovalbumin, OVA). Due to the excellent
cores and lipophilic lipids bind hydrophilic and hydrophobic drugs biocompatibility of AuNWs nanomotors, it can improve antigen
in liposomes, which are phospholipid vesicles. Targeting on cancer cross-presentation and cellular immunity and thus promote
therapies, liposomes are commonly used as carriers for targeted immune efficiency of vaccines (Wang J. et al., 2021). In terms of
delivery. Inorganic nanoparticles are known to carry drugs via chemical drives, bubble propulsion mechanisms have received the
surface coupling (Wang X. et al., 2021), dendritic polymers with most attention to date. By adjusting the intensity and pulse of UV
shell-core properties (Kheraldine et al., 2021), as well as polymeric irradiation, Mou et al. can remotely control whether or not bubbles
nanoparticles. Among the propulsion sources for drug-delivery are generated, while utilizing the photocatalytic water redox reaction
nanorobots are magnetically driven (Hu et al., 2020; Sindhu on TiO2/Pt under UV irradiation16. It is important to note;
et al., 2021; Zhao et al., 2022; Li et al., 2023), which uses a however, that bubble recoil propulsion does have limitations, and
magnetic field to propel the device, optically driven (Dong et al., the floating bubbles are unstable in most physiological environments
2016), which utilizes semiconductor-based photoinduced catalysis outside of the gastrointestinal tract of human (Jang et al., 2019). As a
to provide propulsion, acoustically driven (Ahmed et al., 2015), result of their inherent limitations, nanorobots remain challenging
chemically driven (Mou et al., 2016), and biologically driven (Park in design and preparation today, including complex fabrication
et al., 2017; Halder and Sun, 2019). An external field drive for micro- techniques, difficulties in surface modification, difficulties in
nanorobots can be provided by magnetic, optical, and acoustic flowing biofluids, and poor biocompatibility or poor
waves. It has the advantages of easy adjustment and high biodegradability, depending on the materials (Zhang et al., 2020).
controllability, but it relies more heavily on off-field devices for There are many applications of nanomaterials, including drug
power. Among these types of drives, magnetic drives are the most delivery, medical imaging, and other fields, that benefit from their
commonly used, and compared with other micro-/nanorobot drive unique physicochemical properties and photothermal effects,
methods, magnetic drives influenced by magnetic field gradients and namely, its small size, light weight, easy adjustment, strong
magnetic field torques possess the characteristics of being easy to penetrationand non-destructive penetration into biological
acquire, easy to adjust magnetic fields, and capable of penetrating tissues. In recent years, nanomedicine has shown great potential
into biological tissues without significant damage. It can be used in a for applications. For instance, nanomedicines have been widely
variety of liquid environments, which is the relatively most mature applied. Since the first nanomedicine doxorubicin (DOX) was
driving method. Micro-/nanorobots fabricated with magnetic drive introduced in 1995 (Barenholz, 2012), researchers have developed
as the power module can be broadly classified into spiral-propelled a wide range of nanomedicines to date, including paclitaxel albumin
micro-/nanorobots (Walker et al., 2015), oscillating magnetic field- nanoparticles (Chen et al., 2021) and elitecan liposomes (Wang T.
driven flexible micro-/nanorobots (Li et al., 2017; Xin et al., 2019; Liu et al., 2021), which are used to treat a variety of serious diseases. The
J. et al., 2021; Ji et al., 2021) and other types of magnetic field-driven use of nanomedicine for disease monitoring and minimally invasive
micro-/nanorobots, such as gradient magnetic field-driven micro-/ surgery is among the many clinical applications of nanomedicine.
nanorobots (Li et al., 2016; Wang et al., 2022). Researchers are also Consequently, the development of nanomedicine in disease
attempting to create micro-/nanorobots using a combination of monitoring and minimally invasive surgery is not to be
magnetic drive and other drive methods at the same time due to the underestimated, as nanorobots have many advantages over
features such as easy adjustment of magnetic fields and non- conventional robots, including the ability to monitor and treat
destructive penetration into biological tissues. This can be lesions more efficiently (Mir et al., 2017).
accomplished by giving certain magnetic properties to micro-/
nanorobots while applying other driving methods. In recent
years, more types of magnetic nanorobots have been designed, 1.1 Clinical applications of nanomedicine
Yu et al. have fabricated trimeric nanorobots using three
magnetic Janus colloids of different diameters (Yu et al., 2022). Research for nanotechnology application in the medical field has
Inspired by the biological claws of tardigrades, Li et al. have designed focused on the diagnosis of diseases, targeted delivery, and
a magnetically driven swimming microrobots with claw geometry minimally invasive surgical procedures. As a result of their small
and a red blood cell (RBC) membrane camouflage on its surface. It size, light weight, flexibility, and nondestructive penetration into

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biological tissues, micro-/nanorobots achieve results that are development of resistant tumor variants. In addition to
difficult or even impossible to achieve by conventional mean traditional anticancer drugs, nanomedicines can be combined
(Fadeel and Alexiou, 2020). In terms of chemical reactivity, together to enhance delivery, retention, and release of these drugs
fluorescence, magnetic permeability, and electrical conductivity, into target cells and tumor tissues, thereby increasing the therapeutic
nanomaterials demonstrate significant differences, and these effectiveness of cancer treatment. The combination of SOR and
properties could lead to significant advancements in the adriamycin has been proven to provide better therapeutic effects in
development of new drugs (Jacob et al., 2020). Imaging patients with advanced hepatocellular carcinoma in clinical trials.
techniques in the biomedical field are used to monitor the Using a hybrid lipid-polymer nanoparticle containing a tumor-
pharmacokinetics and pharmacodynamics of nanomedicine, as targeting peptide (iRGD), Zhang J. et al. (2016) developed a
well as to improve nanomedicine-based therapeutic regimens in (DOX) and SOR delivery system containing iRGD (see
preclinical research (Tuguntaev et al., 2022). Figure 1A). In contrast to single drug delivery, the hybrid
delivery system resulted in greater bioavailability of the drug,
1.1.1 The use of nanomedicine in the treatment of improving the effectiveness of the anti-tumor treatment. The
major diseases results of this study demonstrate that nanoparticles combined
With the unique advantages of nanotechnology, targeted drug with clinical anticancer drugs are capable of enhancing anti-HCC
delivery has become a reality. By delivering therapeutic drugs efficacy, which is a direction of future research. In addition to the
through nanocarriers and targeting their delivery to the focal combination of nanoparticles and anticancer drugs, the
area, it is possible to increase the concentration of therapeutic combination of therapeutic nucleic acids and nanoparticles has
drugs in the focal area while minimizing side effects and damage also shown promise for application. In the research of Oh et al.
to non-targeted areas. Many nanomedicines have been developed by (2016), DOX bound by electrostatic interaction was delivered
researchers in the last few decades for different diseases, especially through liposomes coated with siRNA, and the combination of
for some major diseases, which have greatly reduced pain and DOX and siRNA inhibited tumor growth (see Figure 1B). Therefore,
economic pressure for patients. synergistic antitumor therapy has the potential to effectively target
tumor cells and improve the antitumor effect, demonstrating its
1.1.1.1 Oncology therapy related applications great potential. A nanodrug (HA @ PDC-DOX2) was also developed
The It is widely recognized that medical nanotechnology is a and synthesized by Wang J. et al. (2020), consisting of peptide-
promising approach to solve cancer challenges. Worldwide, cancer adriamycin as the core and hyaluronic acid as the shell, to enhance
is the leading cause of death, accounting for nearly 10 million (or the stability and targeting capability of PDC-DOX2 (see Figure 1C).
nearly one in six) deaths, according to a report published by the A new gold nanoparticle (Do-AuNP) was successfully synthesized
World Health Organization (WHO). Among the conventional from the extract of Dendrobium (DO), a traditional Chinese
cancer treatments, surgical resection, radiotherapy, and medicine. Experimental results show Do-AuNP has better anti-
chemotherapy are the most common. The current conventional tumor efficiency as compared to gold nanoparticles in either vitro or
treatment for cancer kills cells indiscriminately in the focal area of in vivo, providing a new approach (Zhao et al., 2021). One of the key
the body, causing severe pain to the patient during the treatment directions in nanomedicine research for the future will be to
procedure (Li et al., 2020). Drug delivery via nanomedicine carriers combine nanoparticles with molecules, therapeutic drugs or
is a viable alternative to conventional chemotherapy which suffers inter-nanoparticles in order to enhance the stability, therapeutic
from poor water solubility, poor tissue targeting, and severe systemic effects, and reduce the toxic effects of nanomedicines.
toxic effects (Kumstel et al., 2020). Nanomedicine carriers increase In addition to being the most common malignant tumor in
drug concentration within the target area and thus improve drug women, breast cancer is also the leading cause of cancer deaths in
utilization and efficacy by increasing the drug concentration in the women. Researchers have developed a variety of nanomedicines
target area. As well, the nano drug carriers can be administered using a variety of materials to solve the problem of serious side
within the tumor vasculature, thereby reducing the drug dose and effects caused by therapeutic drugs. These nanomedicines target
the toxic side effects on other tissues and organs. cancer cells specifically and do not affect normal cells. It has been
In the world, liver cancer is the sixth most common type of reported that Cheng et al. (2021) have developed a novel
cancer. Hepatocellular carcinoma (HCC) has an 18% 5-year survival nanomedicine (CuQDA/IO@HA) containing copper ions and
rate, making it the second most lethal cancer following pancreatic quercetin to specifically target cancer cells via CD44 and induce
cancer. Its insidious onset and insensitivity to chemotherapy make specific cytotoxicity in breast cancer (BRCA)-mutated cancer cells.
its treatment unsatisfactory (Zhang X. et al., 2016). As nanodrugs are More importantly, CuQDA/IO@HA demonstrated no significant
able to increase drug bioavailability and hepatic targeting while adverse effects on normal tissues or organs, demonstrating the
reducing side effects on normal tissues, they offer greater ability to treat cancer cells by integrating metal ions with
possibilities for treating hepatocellular carcinoma when nanomedicines. It is possible to reapply nanodrugs by integrating
conventional therapies are ineffective (Bakrania et al., 2021; metal ions. A number of nanomedicines based on nucleic acids,
Elnaggar et al., 2021). In the field of targeted therapies, sorafenib including DNA and RNA, have been found to be particularly
(SOR) was the first systemic drug to demonstrate efficacy in patients effective when combined with chemotherapy. To enhance the
with advanced HCC and has been used as a first-line treatment for therapeutic efficacy and targeting on breast cancer, Zhan et al.
more than 10 years. SOR alone is unlikely to achieve therapeutic (2019) developed a novel tumor-targeting nanomedicine
expectations because of its inherent toxic side effects and the (AS1411-T-5-FU) that was combined with 5-fluorouracil (5-FU)
development of tumor resistance. This could be caused by the using DNA-based delivery systems (see Figure 2A). As a result, this

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FIGURE 1
(A) Co-delivery of DOX and SOR by iRGD-modified lipid-polymer hybrid nanoparticles (Zhang J. et al., 2016). Reproduced with permission.
Copyright 2016, Nanomedicine: Nanotechnology, Biology and Medicine; (B) Schematic of preparation of Gal-DOX/siRNA-L (Oh et al., 2016).
Reproduced with permission. Copyright 2016, Nanomaterials; (C) Schematic illustration of formation of HA @ PDC-DOX2 (Wang J. et al., 2020).
Reproduced with permission. Copyright 2020, Materials Science and Engineering: (C)

FIGURE 2
(A) Schematic diagram of the structure of the nanomedicine (AS1411-T-5-FU) (Zhan et al., 2019). Reproduced with permission. Copyright 2019, ACS
Applied Materials & Interfaces; (B) Estimated atomic % of detected surface elements (Howard et al., 2022). Reproduced with permission. Copyright 2022,
Small.

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FIGURE 3
(A) Schematic illustration of the preparation for TMZ-FaPec@siRNa micelle and the release of TMZ and siRNa inside cancer cells (Peng et al., 2018).
Reproduced with permission. Copyright 2018, International Journal of Nanomedicine; (B) Preparation process of the nanomedicine (Au/FeMOF@CPT
NPs) (Ding et al., 2020). Reproduced with permission. Copyright 2020, Advanced Science (C) Schematic diagram of the preparation of platelet
membrane-coated docetaxel (DTX)-loaded poly (lactic co-glycolic acid) (PLGA) nanoparticles (PM/PLGA/DTX) (Chi et al., 2019). Reproduced with
permission. Copyright 2019, Journal of Nanoparticle Research.

nanomedicine is capable of targeting and killing breast cancer cells release. As a result of loading nanobots with therapeutic drugs and
more effectively than 5-fluorouracil alone, showing DNA’s potential releasing them in the tumor area, the drug concentration in the focal
as a nanomedicine material. Nucleic acid nanodrugs, however, face area increased and the drug utilization rate improved, and the drug
considerable difficulties in clinical applications due to their poor was also reduced as it was released into other tissues and side effects
biocompatibility and low drug loading efficiency. Alternatively, were reduced (Llopis-Lorente et al., 2019). Therefore, it is apparent
Howard et al. (2022) assembles herpes simplex virus (HSV1716) that nanodrugs are more effective at breaking through the blood-
with magnetic nanoparticles in order to precisely target cancer cells brain barrier than traditional chemotherapy treatments, which
through magnetic actuation (see Figure 2B), preventing antibodies offers more treatment options for those suffering from brain
from attacking the virus in vivo before it can act, allowing the virus to diseases. The benefit of this approach is that it provides a greater
proliferate in cancer cells while accumulating immune cells in the variety of treatment options for brain diseases and achieves a more
tumor, It can improve the treatment effect of disseminated tumors rapid therapeutic effect. Nevertheless, drug resistance is also a
by 50% by promoting antitumor immunity, inducing tumor problem when treating glioma with a single drug. The
shrinkage, and increasing survival in a homozygous mouse model combination of drugs, however, has good performance in treating
of breast cancer. Each material has its own advantages and glioma. The synergistic effect of the combination of therapeutic
disadvantages, and it appears to be a promising direction for drugs and siRNA can significantly improve the anticancer effect in
future research utilizing the advantages of the materials various cancers. In an experiment conducted by Peng et al. (2018), a
themselves to their fullest extent and utilizing chemical coupling targeted nanocarrier carrying temozolomide (TMZ) and anti-BCL-
as a means of circumventing their shortcomings. 2 siRNA was used to assess the physicochemical properties and
It is extremely difficult to treat glioma using conventional release profile of this drug, both in vitro and in vivo (see Figure 3A).
therapy as the blood-brain barrier severely hinders the anticancer Moreover, the drug promoted targeted drug delivery and inhibited
effects of chemotherapy on glioma. However, various specific tumor growth by activating pro-apoptotic genes in cancer cells,
transporters on the blood-brain barrier can be utilized as targets resulting in a significant apoptotic response and prolonging patients’
to deliver tumor drugs using targeted nanoparticle delivery systems survival periods. It is necessary to develop drugs for the treatment of
(Deng et al., 2020).Hortelao et al. designed an experimental brain diseases that are capable of crossing the blood-brain barrier, as
nanorobot which was modified by urease and constructed with well as to evaluate the clinical effectiveness of the drugs and to target
SiO2 as a shell. It can load therapeutic drugs into tumor cells for drug resistance.

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FIGURE 4
(A) Schematic illustration of formation of chitosan-oleic-adipose homing peptide (AHP) micelles complexed with DNA (Banerjee et al., 2020).
Reproduced with permission. Copyright 2020, International Journal of Pharmaceutics; (B) Activation of intestinal L-cell GLP-1 secretion by lipid
nanoparticles (Beloqui et al., 2016). Reproduced with permission. Copyright 2016, Molecular Pharmacology; (C) Diagram of the functional role of
nanofiber-reinforced hydrogel (NFRH) (Qiu et al., 2021). Reproduced with permission. Copyright 2021, Journal of Colloid and Interface Science.

Less than 5% of pancreatic cancer patients survive 5 years after capability, future research should focus on improving the
being diagnosed, making it the world’s deadliest cancer. To enhance bioavailability of drugs, increasing their concentration in tumor
the quality of life and prolong the survival time of patients with sites, addressing possible drug resistance, and increasing their
pancreatic cancer, Gao et al. (2020) proposed delivery of drugs by therapeutic potential.
ultrasound-targeted microbubble destruction (UTMD), which has
significantly improved the therapeutic effect on patients with 1.1.1.2 Endocrine disease treatment applications
advanced pancreatic cancer. Due to its high biological toxicity, Our standard of living has been improving in recent years, and
however, it has some limitations when applied to patients who the lifestyle and diet structure have also been changing. As a result,
are in good physical condition because it places high demands on the incidence of diabetes mellitus (DM) and other diseases has been
their physical function. As reported by Ding et al. (2020), a hybrid increasing, while traditional hypoglycemic drugs have proved
nanodrug was fabricated (Au/FeMOF@CPT NPs) with metal difficult to treat diabetes, causing great inconvenience to patients
organic backbone nanoparticles (MOF) and gold nanoparticles (Vessby et al., 2000). Additionally, diabetic patients are more likely
(Au NPs) (see Figure 3B), which improved the stability of the to require a prolonged hospital stay and have a higher cost of
nanodrug in the organism. It was effective because cancer cells hospitalization, particularly if they have chronic complications
contain high concentrations of phosphate, resulting in the drug’s (Karahalios et al., 2018). For the purpose of alleviating the side
complete release. Even though gold nanoparticles are one of the least effects associated with long-term insulin injections and the
toxic metal nanoparticles, high concentrations may be genotoxic, administration of first-line diabetes treatments, including
and drug safety needs to be considered as well (Desai et al., 2021a). biguanides, sulfonylureas, and glycosidase inhibitors, a variety of
Nanomedicines are also being investigated for their potential nanoparticle-based delivery systems have been developed to replace
therapeutic applications in the treatment of tumors in other conventional medications (Chatzipirpiridis et al., 2015; Wang et al.,
organs, including the lung (see Figure 3C) (Chi et al., 2019; 2018). According toBanerjee et al. (2020), plasmid lipocalin
Wang S. et al., 2020), the esophagus (Chen et al., 2020; Salapa (pADN)-based nanodrugs were developed for treating insulin
et al., 2020), and the cervical region (Sadoughi et al., 2021; Venkatas resistance in type 2 diabetes in experiments with diabetic rats
and Singh, 2021). Considering nanomedicines’ excellent targeting (see Figure 4A). They avoided enzymatic degradation of the gene

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product and significantly improved insulin sensitivity for up to urgently needed to combat the encroachment of thrombotic disease
6 weeks, which is an effective therapeutic method. Due to the in patients. Researchers have thus turned their attention to the
pleiotropic nature of the secreted glucagon-like peptide (GLP), treatment of thrombosis after nanomedicines were first introduced
L cells have attracted the attention of researchers, as Beloqui for the treatment of oncological diseases. Worldwide, ischemic
et al. (2016) A nanostructured lipid carrier was added to L cells, stroke is one of the leading causes of severe disability and death,
and the experimental results showed that nanostructured lipid posing a serious public health problem as well as an economic
carriers can increase GLP-1 secretion in murine and human L burden on families of patients. Blood supply to the brain from blood
cells, which results in increased GLP-1 secretion for diabetes vessels is impeded by thrombosis, resulting in a sudden reduction in
treatment purposes. In order to treat diabetes, exosomes can be cerebral blood flow caused by a series of pathological changes. These
used as nanomaterials (see Figure 4B). It has been found that these changes ultimately lead to cerebral ischemia, which can result in
agents are capable of influencing both glucose and lipid levels, severe disability and even death (Ma et al., 2021). Consequently, a
primarily through promoting glucose metabolism, enhancing variety of nanomedicines have been developed with the goal of
lipid metabolism, and reducing lipid deposition (Ashrafizadeh improving the effectiveness and precision of thrombosis treatments
et al., 2022). Therefore, they can serve as a new strategy for the (Su et al., 2020). Timely and effective thrombolytic therapy is of
treatment of diabetes. great clinical significance, and nanomedicines such as liposomes,
A major focus of current research is the use of nanomedicines to polymer nanoparticles, and magnetic nanoparticles offer great
treat diabetic complications, in addition to diabetes itself. Patients potential (Liu et al., 2018). Furthermore, Xu et al. (2019)
with diabetes are at risk for a variety of complications, including developed a dextran-derived polymeric nanoparticle-based
diabetic foot, diabetic neuropathy, diabetic nephropathy, diabetic nanocarrier (tP-NP-rtPA/ZL006e) for simultaneous delivery of
retinopathy, etc. (Desai et al., 2021b; Balogh et al., 2022) One of the tissue fibrinogen and dextran-derived polymeric nanoparticles
most common, serious, and expensive complications of diabetes is (see Figure 5A). Compared to conventional free drugs, this
diabetic foot. As a result of hyperglycemia and abnormal glucose nanodrug reduced the ischemic area more effectively in in vitro
metabolism, diabetic patients develop lesions, neuropathy, and and in vivo experiments. By contrast, the small extracellular vesicle
infection, making diabetic foot wounds difficult to heal and (sEV)-based drug delivery system developed by Loch-Neckel et al.
leading to long-term inflammation (Tatulashvili et al., 2020). In (2022) is endogenous nanovesicles that have excellent targeting
the case of diabetic feet, conventional treatment methods, such as capabilities and are naturally biocompatible (see Figure 5B).
blood glucose control and wound debridement, fail to heal the These devices are more advantageous in treating CNS diseases,
wound in a timely manner, and once infection occurs untreated, providing greater benefits for the treatment of Alzheimer’s disease,
amputation is the only option (Mariadoss et al., 2022). Therefore, a brain tumors and other diseases, as they can cross the blood-brain
drug capable of improving poor wound healing is urgently needed barrier and target specific nerve cells. Nanomaterials have also
for diabetic. There has been some discussion regarding the potential shown great potential when combined with traditional Chinese
value of nanomaterials in wound healing and infection control in medicine. Salvianolic acid B(SAB), a water-soluble phenolic acid
this regard (Pormohammad et al., 2021; Simos et al., 2021). The derived from Salvia miltiorrhiza, a traditional Chinese medicine.
development of polymeric, metallic, and ceramic nanomaterials for According to Zhang S. et al. (2022), the RR@SABNPs are a brain-
the treatment of acute and chronic wounds has been found to targeted bionanopharmaceutical made of bovine serum albumin
accelerate the regeneration of damaged dermal and epidermal nanoparticles that contain salvianolic acid and functionalized red
tissues (Parani et al., 2016). Nanoparticles of silver (AgNPs) blood cell membranes that contain salvianolic acid. In addition to
synthesized by Varaprasad et al. (2010) are suitable for use as stability, it is biocompatible as well. Influenced by single-cell
antimicrobial dressings and wound dressings, which represents organisms, Zhang et al.propose a strategy to use programmed
an important advancement in the field of antimicrobial dual-ion alternating magnetic fields to enable amoeboid microrobots to
technology. By disrupting bacterial biofilms and causing aggregation more effectively deliver thrombolytic drugs and unblock embolic
of blood cells and platelets, the peptide-modified NFRH developed vessels (Zhang et al., 2023).
by Qiu et al. (2021) may accelerate wound healing by disrupting Furthermore, in a mouse model of infarction, the drug
bacterial biofilms (see Figure 4C). A growing number of diabetic significantly scavenged excess reactive oxygen species and
patients are living in China, which has led to an increased need for reduced infarct size. It is anticipated that the number of patients
treatment of diabetes and its complications, especially the severe who suffer from severe disability or even death as a result of
complications of diabetes. thrombosis will be greatly reduced.

1.1.1.3 Circulatory system therapeutic applications 1.1.2 Other disease treatment related applications
The pathogenesis of many diseases, including deep vein Nanomedicine has also demonstrated promising results in the
thrombosis, pulmonary embolism, and ischemic stroke, involves research of diseases other than tumors and blood clots mentioned
thrombosis (Priya et al., 2021). In clinical practice, antiplatelet above. As the sixth leading cause of death in humans, pneumonia is
agents, anticoagulants, and fibrinolytic drugs are commonly used caused by a variety of pathogens such as bacteria, viruses, and fungi
in the treatment of thrombosis, including arterial and venous that cause damage to lung tissue or interstitial lung. Despite their
thrombosis (Loyau et al., 2018; Khoukaz et al., 2020). In contrast, effectiveness in treating common pneumonia, conventional drugs
traditional thrombolytic drugs have a short half-life, low are less effective in treating some critically ill patients, such as those
bioavailability, poor targeting, and low output efficiency, and the with acute lung injury. In light of this, the development of new drugs
treatment must be repeated multiple times. An efficient drug is for the specific treatment of critically ill patients is one of the most

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FIGURE 5
(A) Main components of the tP-NP-rtPA/ZL006e (Xu et al., 2019). Reproduced with permission. Copyright 2019, ACS Nano; (B) Schematic illustration
of formation of sEV biogenesis (Loch-Neckel et al., 2022). Reproduced with permission. Copyright 2022, Front. Pharmacol.

hotly debated topics in current research (Muhammad et al., 2022). developed as a receptor-targeted nanomedicine for the treatment
According to Mukhaerjee et al., silver Prussian blue (PB) analog of human central nervous system disorders. (Pardridge, 2020).
nanoparticles (SPBANPs), a new nanopharmaceutical formulation
developed by combining PB with silver salts (silver nitrate). The
SPBANPs demonstrated excellent antibacterial activity in Gram- 1.2 Diagnostic applications of nanomedicine
negative bacteria (Escherichia coli, Klebsiella pneumoniae, and
Pseudomonas aeruginosa) and Gram-positive bacteria (Bacillus Through the advancement of nanotechnology, nanomaterials of
subtilis) (Mukherjee et al., 2020). A worldwide pandemic of various types, shapes, and sizes are being applied to biosensors in
COVID-19 has caused the development of vaccines, and order to enhance their sensitivity and accuracy in detecting diseases
nanotechnology has been an integral part of the development of (Spychalska et al., 2020). Salahandish et al. (2018), for instance, used
efficient, safe, and relatively affordable vaccines based on graphene, a material which is highly thermally stable and has good
nanomedicine principles in order to control the pandemic (Al- gas barrier properties. For the detection of miRNA-21, which is a
Hatamleh et al., 2021; Shapiro, 2021). It has been determined that breast cancer marker, a graphene-based (NFG) nanosensor with
vaccines based on nanomedicine principles will be effective, safe, silver nanoparticles (AgNPs) is developed with high sensitivity,
and cost-effective in the fight against the COVID-19 pandemic which could be useful for the early diagnosis of breast cancer
across the globe. Nanotechnology has played an integral part in (see Figure 6A). Zhang et al. proposed the use of magnetic
developing such vaccines (Tang et al., 2017; Niu et al., 2021). properties of iron oxide nanoparticles as MRI contrast enhancer.
William M. Pardridge develops a drug that both encapsulates Such particles can form magnetic fields and are easily deformed and
plasmid DNA encoding a therapeutic gene and crosses the manipulated. This method makes MRI of lesion sites easier to
blood-brain barrier (BBB). The drug uses Trojan horse liposomes visualize and also effectively reduces the amount of contrast
(THL), also known as polyethylene glycolated immunoliposomes, agent used (Zhang Z. et al., 2022).
formed by encapsulation of plasmid DNA inside polyethylene During the treatment of diabetes, it is imperative to develop
glycolated liposomes with a net anionic charge, and THL is new methods of monitoring blood glucose levels, since the

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Zhao et al. 10.3389/fbioe.2023.1219054

FIGURE 6
(A) Schematic illustration of formation of nanocomposite fabrication (Salahandish et al., 2018). Reproduced with permission. Copyright 2018,
Biosensors and Bioelectronics; (B) cobalt-nickel (CoNi) microtube steered along a vein in a porcine eye (Chatzipirpiridis et al., 2015). Reproduced with
permission. Copyright 2015, Advanced Healthcare Materials.

current methods are relatively cumbersome to diagnose and 2 Nanomedicine faces numerous
monitor. Biosensors based on nanoparticles offer increased challenges
glucose monitoring sensitivity, allowing clinicians and
researchers to quantify diabetes levels and make further In Micro-/nanorobots are much smaller than macro-robots and
diagnoses with greater accuracy (Kovatchev, 2018; Wang Y. they can pass through biological tissues to reach the lesion, allowing
et al., 2021). precise micro-operations and accurate drug delivery in complex
biological environments. There is a great deal of potential in
nanotechnology for the future. Medical nanotechnology still faces
1.3 Surgical procedures utilizing many problems in practical clinical applications despite the
nanomedicine numerous breakthroughs and innovations in nanotechnology and
materials science in recent decades.
It is also possible to use nanomedicine technology in minimally
invasive surgical procedures. Since micro-/nanorobots are small and 1) Micro-/nanorobots are used to deliver nanomedicines due to
lightweight, they offer increased flexibility in narrow biological their small size, allowing them to penetrate deep into biological
tissue environments. Macro-/nanorobots can perform a number tissues with less damage and to cross the blood-brain barrier to
of precise micro-operations and reduce tissue damage during reach sites which conventional drugs are unable to reach.
surgery, as well as perform functions that macro-/nanorobots However, their drug-carrying capacity is slightly insufficient,
cannot. and they can also have difficulty transporting large molecules.
In a live rabbit eye, Chatzipirpiridis et al. successfully Therefore, further research is needed to promote nanorobots to
operated a micro-/nanorobot wirelessly by rotating around break through in vivo biological barriers and achieve multi-drug
its axis and injecting a 23-gauge needle into the central carriage more effectively.
vitreous fluid (see Figure 6B) (Chatzipirpiridis et al., 2015). 2) A crucial aspect of the development process is the selection of
Researchers insert nanorobots into rat brains through the nose nanomaterials. In particular, the preparation of micro-/
to perform different types of movements by regulating the nanorobots that utilize naturally occurring microorganisms in
magnetic field. They are currently investigating the insertion nature must address the problem of life support for
of magnetic microrobots into neural tissue to induce behavioral microorganisms as well as the provision of nutrients necessary
changes in small mammals (Soto et al., 2020). In the future, it for their growth. It is important to consider the toxicity,
may be possible to develop micro-/nanorobots that can treat degradability and applicability of the materials used in the
diseases in other narrow areas of the human body. In this study, preparation of micro-/nanorobots using artificial technologies
it has been shown that micro-/nanorobots can significantly (such as 3D printing) and whether they can be widely used.
reduce tissue damage during surgery owing to their own 3) Depending on the degree of lesions, the appropriate amount of
properties, and their use in minimally invasive surgery holds nanomedicine should be released, as well as how to provide timely
great promise. It has demonstrated excellent potential in and accurate feedback regarding whether the expected effect has been
experimental studies, even though it has not yet been able to achieved. When the drug has been delivered and released into the
be scaled up to the clinical setting. body, it should be completely and safely discharged outside the body.

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Zhao et al. 10.3389/fbioe.2023.1219054

4) Currently, cross-disciplinary cooperation and exchange are Funding

insufficient; basic research needs to be improved, and some
important theoretical issues involving nanomedicines still This work is supported by The President’s Fund of the Fourth
require further study. Affiliated Hospital of Harbin Medical University
(HYDSYYZ201502); Natural Science Foundation of Heilongjiang
Province (LH 2020H063); Outstanding Youth Fund of the Fourth
3 Overview and outlook Hospital of Harbin Medical University (HYDSYYXQN202008);
Heilongjiang Provincial Academy of Science and Technology
With continuous innovations and breakthroughs in nanomedicine Cooperation Project (YS18C06); Heilongjiang Province
technology, diagnosis and treatment at the microscopic level are Postdoctoral Fund (LBH-Z21170); Sichuan Provincial Western
increasingly becoming a reality, and nanomedicine technology is Psychiatric Association’s CSPC Leading Scientific Research Project.
widely used in clinical treatment, disease diagnosis and other
medical fields. However, nanomedicine does not yet have a perfect
solution to many major diseases, and safety issues and other problems Conflict of interest
remain challenging. However, the system is not yet perfect and some
problems still exist. In the field of nanomedicine technology, solving the The authors declare that the research was conducted in the
material, functional and safety-related problems of nanocarriers is still a absence of any commercial or financial relationships that could be
hot spot for research with wider potential applications, which deserves construed as a potential conflict of interest.
more in-depth exploration and research.

Publisher’s note
Author contributions
All claims expressed in this article are solely those of the authors
ZQ and CN conceived the idea of the study. SX and CN analyzed and do not necessarily represent those of their affiliated
the data. YL and LW interpreted the results and wrote the paper. ZQ organizations, or those of the publisher, the editors and the
and CN discussed the results and revised the manuscript. All authors reviewers. Any product that may be evaluated in this article, or
read and approved the final manuscript. All authors contributed to claim that may be made by its manufacturer, is not guaranteed or
the article and approved the submitted version. endorsed by the publisher.

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