Over the past three decades, platelet-rich plasma (PRP) has been used for surgeries, sports-related injuries, patients on chemotherapy and radiotherapy, children with acute lymphoblastic leukemia, patients with chronic renal failure, and many situations in which individuals suffer from dysfunctional or insufficient platelets . Platelets (Fig. 1) are very small discoid-shaped cells of 1–2 mμ in diameter, which circulate in the bloodstream along with other blood cells. These anucleate cells principally participate in hemostasis and plugging holes to prevent bleeding in blood vessel walls [2, 3]. Platelet storage lesion (PSL), a complex biological event that combines collection and storage conditions, limits the shelf time of platelet bags between 3 and 7 days at 22–24°C in many countries. Indeed, an extended storage period may increase the risk of bacterial transmission to patients due to the optimal storage conditions for bacterial growth, loss of platelet structure, and function
Recently, nanotechnology has been widely used in various fields such as biology, industry, and medicine, but the safety of different nanoparticles (NPs) is still a point of conflict [6-9]. Researchers have studied the effects of different nanoparticles on the blood cells. Some nanoparticles, such as carbon and gold nanoparticles, affect platelet aggregation and lead to vascular thrombosis. However, polymeric nanoparticles, owing to their biocompatibility, as well as the high bonding capacity of the functional groups and surface modification, have been able to show higher platelet compatibility in some areas . Polymeric nanoparticles are a group of nanoparticles that can be synthesized from natural, synthetic, biodegradable, or non-biodegradable polymers of nanometer size. Owing to the possibility of high surface modification in these nanoparticles, they are used to reduce the side effects during drug delivery and increase the biocompatibility of nanoparticles for various applications. These nanoparticles are usually biodegradable and classified into two classes based on their properties: i) agro-polymers (e.g., polysaccharides and proteins) and ii) biopolystyrenes (e.g., microorganisms and synthetic polymers). Biodegradable synthetic nanopolymers are also divided into two groups: i) synthetic [e.g., polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), polyanhydride, polycaprolactone (PCL), and poly(alkyl cyanoacrylate) (PACA)] and ii) natural (e.g., alginate, chitosan, cellulose gelatin, pullulan). However, there are also non-biodegradable types of synthetic nanopolymers, such as poly(methyl acrylate) (PMA) and polyamidoamine (PAMAM) .
In this regard, in the present study, we investigated the recent findings on the effects of different polymeric nanoparticles, namely chitosan, dendrimers, polyethylene glycol, and liposomes, on the structure and function of platelets, on platelet function.
Chitosan (Fig. 2) is obtained from the partial deacetylation of chitin and is composed of acetylated units of N-acetyl-D-glucosamine and deacetylated units of β-(1→4)-linked D-glucosamine. This nanopolymer is a cationic natural biodegradable polysaccharide that possesses properties such as biocompatibility and antimicrobial activity with low immunogenicity [12-17]. Owing to the positive surface charge, these nanoparticles can often react with negatively charged surfaces in blood, such as cell membranes and amino acids in serum proteins . Naturally, platelets as blood cells can be affected by these nanoparticles depending on the properties of the polymer, such as composition, mobility, charge density, and the degree of hydrophilicity/hydrophobicity. The interaction between positively charged chitosan and platelets, which leads to an increase in platelet adhesion and activation, has been widely used in wound dressing [19-23]. Gu
In addition, He
The contact system is the effect of polymers on blood systems after the absorption of proteins, which can alter the function of proteins and related systems such as coagulation and inflammation . By investigating the impact of the contact system on the interaction of positively charged CS and platelets, Lord
In another study, Chung
Thus far, the encapsulation of some thrombotic compounds has increased their properties. In this context, ellagic acid was encapsulated in CS-NPs by Gopalakrishnan
In a study conducted by Ramtoola
In addition, the positive surface charge of chitosan can be reduced in various ways, and new properties can be created in this NP using this approach. In this regard, Shelma and Sharma  synthesized lauroyl sulfated chitosan (LSCS) NPs, which are amphiphilic derivatives of CS, and then assessed their effects on hemocompatibility. They described that this CS derivative was more blood-compatible than CS. They inhibited the hemolytic activity of CS on RBCs and stopped morphological changes and aggregation in platelets. As a result, the clotting time increased when using this derivative compared to CS.
In 2011, Jiang
In addition, Kim
Table 1 represents the results in detail.
Dendrimers are 3D-hyperbranched, monodisperse, and nanosized structures, which are composed of a symmetric core, branched functional groups, and internal cavities . These molecules can form multiple bonds with different drugs and compounds through functional groups or encapsulate them through their inner cavities [37, 38]. Dendrimers are divided into several types based on the surface charge (cationic, neutral, and anionic), generation, and type of functional groups. Dendrimers with different properties can have different effects on platelets, some of which are reviewed here. One of the most popular types of cationic dendrimers is the PAMAM dendrimer (Fig. 4). The core of this dendrimer is composed of ethylene diamine (EDA) or ammonia, and the branches contain amidoamine residues. A positive charge density is formed on the surface of the PAMAM dendrimers owing to the presence of many NH2-terminated groups. As a result, this positively charged surface can interact with the negatively charged surface of platelets and other blood components. Thus, they are usually not blood-compatible, without any surface modification. In two preliminary studies, Dobrovolskaia
The effect of surface charge on PAMAM-platelet interaction was also determined in an
The evaluation of cationic PAMAM impacts on platelets was carried out in two separate
In addition, Chitlur
Additionally, Šemberová  assessed the influence of G3 and G6 PAMAM dendrimers as a function of generation and surface charge on the expression of CD62P marker of platelets in an
In another study, Aisina
In addition, Enciso
In a study conducted by Fu
However, these cationic dendrimers can be modified by coating agents to synthesize anionic and neutral forms with less cytotoxic effects.
In another study conducted by Liu
In addition, Alavi
In another study, Li
Some studies have also inhibited ADP-mediated platelet aggregation by binding adenosine receptor antagonists to dendrimers .
Another important cationic dendrimer in the field of drug delivery is polypropylene imine (PPI). The central core of PPI is composed of EDA and diaminobutane (DAB), and its internal structure contains alkyl and tertiary amine residues. Similar to PAMAM, PPI also has a positive surface charge and can interact with negatively charged components and cells in the blood. To reduce the cytotoxicity of these positively charged dendrimers, surface modification studies have been conducted.
To selectively deliver the drug to chronic lymphocytic leukemia (CLL) cells, Franiak-Pietryga
Cationic carbosilane dendrons are cationic dendrimers that can affect platelets. In this regard, the blood compatibility of gold nanoparticles stabilized with carbosilane dendrons was determined by Peña-González
In the study by Pedziwiatr-Werbicka
In addition, the influence of cationic carbosilane phosphorus-containing dendrimers and their complexes with siRNA and oligodeoxynucleotides (ODN) was examined on platelets by Dzmitruk
In the field of surface modification, Barrios-Gumiel
In addition to cationic dendrimers, anionic types are usually more blood compatible. Anionic linear globular dendrimers (ALGDs) are anionic dendrimers with low toxicity, high biocompatibility, biodegradability, and water-solubility [64-66]. They are synthesized using cost-effective methods and have a low dispersion index. Structurally, their core is PEG, and their outer branches have carboxyl groups. The negative charge of ALGD reduces repulsive forces and cell binding, thereby decreasing the interaction between loaded drugs and receptors. As a result, the viability of cells improves because they can easily remove deleterious components. The cellular mechanism of ALGD uptake is not clear, but dendrimers usually enter cells via receptor-mediated internalization .
However, they were not able to induce hemolysis in the study by Alavidjeh
Another anionic dendrimer is the polyglycerol dendrimer (PGLD), which was used in the study by Fernandes
These synthetic, hydrophilic, and biocompatible nanopolymers (Fig. 5) are composed of petroleum [70, 71]. PEGylation has received considerable attention in the field of platelet storage. According to previous studies, PEGylation can reduce the storage temperature of platelets to 4°C and even sub-zero temperatures without inducing any changes in platelet structure and viability. In addition, PEGylated platelets have also been used to prevent bacteria from reacting with platelets in platelet bags and to increase transfusion safety .
In this context, a methoxy-PEGylation (mPEG) approach was applied by Scott
In another study, Tarrand and Andersson  examined the effect of adding low molecular weight PEG (100–500 g/mol) to the preservation medium of platelets.
According to their patent study, PEG-treated platelets showed less platelet aggregation than the control group. Platelets in PEG medium could not bind to macrophages, indicating an increase in the duration of platelet circulation in the blood. In an
In addition, Maurer
Because platelets are typically stored at 22–24°C, Platelet products are decent places for bacteria to grow. Bacterial growth in platelet bags increases platelet aggregation and poses a risk to blood transfusions .
In this regard, Greco
In addition, PEGylation has been used to reduce the toxicity of other nanopolymers on platelets. As mentioned earlier, Liu
In addition, Alavi
In another study, Kim
The effect of PEGylation of liposome-encapsulated hemoglobins (LEHs) on their thrombocytopenic reactions was investigated in two different studies [79, 80]. Srinivasan
The impacts of different sizes and concentrations of PEGylated PLGA NPs on platelets were determined by Bakhaidar
In addition, in another study , which determined the effects of various sizes of PLGA-PEG NPs on PRP, they also revealed that 113 nm PLGA-PEG NPs did not affect ADP-mediated platelet aggregation, while 321 and 585 nm NPs inhibited ADP-induced platelet aggregation at concentrations above 0.25 mg/mL. In total, they reported that PEGylated PLGA NPs were platelet compatible. The details are listed in Table 1.
Liposomes are the first FDA-approved carriers for anticancer drugs because of their biodegradability, biocompatibility, non-toxicity, and amphiphilicity. Structurally, they are spherical and consist of two lipid layers [83-85]. Their properties vary based on the lipid composition, size, charge, and synthetic methods.
To design highly selective thrombolytic agents, Srinivasan
To improve the coagulability of platelets, Chan  encapsulated thrombin into liposomes, which could be endocytosed by platelets
In this study, the reported effects of polymeric nanoparticles on platelets between 2010 and 2020 were reviewed. The results of studies have shown that platelet membrane charge is negative; therefore, nanoparticles with positive charge facilitate platelet-platelet reactions by neutralizing the repulsive force between the negatively charged surfaces of cells and creating cross bridges among them, which causes platelet aggregation [40, 46, 68, 92]. Prevention of platelet aggregation during storage depends on other factors, such as size, shape, molecular weight, hydrophobicity, and concentration of nanoparticles. Therefore, nanoparticles with more surface negative charge, smaller size, lower molecular weight, at lower concentrations, and hydrophobic nature can be more effective in preventing platelet aggregation in platelet concentrates during storage [40, 44, 46, 48]. The size and charge of nanoparticles play an important role in increasing platelet survival. For example, dendrimer nanoparticles with smaller sizes and negative charges prevent platelet aggregation and improve platelet function in platelet products, while large cationic dendrimers usually induce platelet aggregation through the electrostatic interaction of their highly positively charged surface and the negative points (e.g., acid sialic) on the surface of cells . Therefore, it seems that surface modification of nanoparticles with nanoPEGylation can significantly increase platelet survival by inhibiting NP-induced platelet aggregation in platelet products [50, 77-82]. In addition, PEGylation of platelets can improve platelet quality during storage [72-74]. As mentioned earlier, cooling platelets during storage time induces PSLs in them, which results in altered morphology, aggregation, granule release, survival, and the expression of surface markers in cold-stored platelets, while storage of platelets at 22–24°C protects platelets from these lesions . However, this temperature increases the possibility of bacterial growth in platelet products, which reduces the safety of blood transfusions [72, 74, 75]. In addition, α subunits of glycoprotein Ib (GPIbα) on the surface of platelets can irreversibly change during cold storage, resulting in rapid clearance of cold-stored donor platelets by macrophages . On the other hand, PEGylation of platelets has been able to prevent the formation of PSTs in cold-stored platelets. PEGylated platelets have normal function and shape, and they significantly decrease microaggregation in cold-stored platelets (stored at 4°C and -80°C) [72-74]. The effectiveness of PEGylation in preserving platelets reduces the disposal of blood products. The storage of platelets at cold temperatures can also decrease microbial growth and enhance blood transfusion safety. Moreover, PEGylated platelets cannot be rapidly cleared from the bloodstream by macrophages . In addition, PEGylation of blood cells depends on PEG size. While larger polymers (20 kD) can be useful for PEGylation of RBCs and WBCs, a shorter polymer is better for platelets (2–5 kD) . Furthermore, although liposomes have been widely used to improve the storage conditions of erythrocytes, there is a paucity of information on the effects of these nanoparticles on platelet storage [93-97].
Based on the data collected from 2010 to 2020, we concluded that the presence of dendrimer nanoparticles with smaller size and negative charge, with low molecular weight and low concentration along with PEGylation, can increase the stability and survival of platelets during storage. In addition, PEGylation of platelets is a promising approach to improve the quality of platelet bags during storage.
No potential conflicts of interest relevant to this article were reported.