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Nanotechnology offers various nanostructures/nanoformulations in the field of nanomedicine with exceptional physical, chemical, mechanical, electrical, magnetic, and biologic properties. Nanomaterials as a key component of nanomedicine extend many benefits due to their nanoscale properties as shown in Figure 1.1. Medical developments in cancer are among the most promising treatment methods in nanomedicine. So, the additional emphasis on cardiovascular, autoimmune, psychiatric, viral, and genetic and rare diseases is a positive development within the scientific community in nanomedicine. Another new field of high promise for nanomedicine is RNA‐based synthetic vaccines (De Jong and Borm 2008; Utreja et al. 2020).

In recent years, nanomedicines have been well known because nanostructures can be used as delivery agents by encapsulating or adding medicinal drugs and distributing them more specifically with a controlled release to target tissues. More than 50 nanoformulations have been approved by the FDA since 1995 and are currently on the market for a variety of indications. The commonly approved nanoformulations are liposomes, nanocrystals, iron colloids, protein‐based NPs, nanoemulsions, and metal oxide NPs. The recent acceptance of three primary nanomedicine drugs (e.g. Onpattro®, Vyxeos®, and Hensify®) by the FDA has demonstrated that the field of nanomedicine is specifically capable of developing products that transcend crucial obstacles in conventional medicine in a special manner (Martins et al. 2020). It also offers new drug‐free clinical effects through the use of pure physical modes of action within the cells, which thereby allows a difference in the lives of patients. In addition, new clinical applications are introduced commercially owing to nanomedicine formulations currently in clinical trials (above 400) unaided or jointly with foremost technologies including microfluidics, biotechnology, photonics, information and communication technology, advanced materials, biomaterials, smart systems, and robotics. Colloidal particles composed of macromolecular compounds in the 1–500 nm size range are NPs that are carriers in which either the active material is dissolved, encapsulated, or adsorbed into the matrix uniformly (Germain et al. 2020).

Figure 1.1 Nanoscale properties and allied benefits of nanomaterials in nanotherapy.

Liposomes are one of the most studied advanced nanoformulations, first described in 1965 for medical applications. They are biocompatible bilayered structures (single or multiple) of 50–500 nm size range composed of either or both synthetic and natural lipids that imitate cell membranes with an empty aqueous interior core. They are classified as multilamellar, oligolamellar, and unilamellar depending upon structural parameters or the number of bilayers formed and the diameter of the resultant vesicles as well as the method of preparation. They are widely used and researched nanoformulations owing to their unique properties and capacity to carry and deliver both hydrophilic as well as hydrophobic therapies in the aqueous core and lipophilic bilayer, respectively. These nanostructures are also considered to boost biodistribution and to make encapsulated medicines, such as low‐molecular weight drugs, imaging agents, nucleic acids, proteins, and peptides, safe in the harsh bioenvironment of ill tissues (Vanza et al. 2020). The biological molecules like monoclonal antibodies, enzymes, and antigens can be delivered by conjugation as ligands on their surfaces (Zeb et al. 2020). Liposomes can exhibit high circulation time, sustained exposure to the site of action, strong diffusion, and penetration activity due to their unique physicochemical properties. However, clearance by RES (reticuloendothelial system), immunogenicity, and opsonization are obstacles in the use of liposomes for drug delivery. However, factors such as EPR effect aspire to improve the functioning of liposomes as drug carriers. Their simplicity of surface alteration makes them more popular in the distribution of medications (Utreja et al. 2020). PEGylated liposomes are developed by surface modification of lipid bilayer through polyethylene glycol (PEG) and are also known as long‐circulating liposomes or stealth liposomes. This decreases the uptake of liposomes by RES due to steric repression of hydrophobic and electrostatic interactions with plasma proteins or cell, thus avoiding its clearance. Various investigators have shown that moderately PEGylated liposomes have increased stability of drugs with longer blood circulation time, poor plasma clearance, and low volume of distribution (Gabizon et al. 1994; Bobo et al. 2016). The liposomal delivery vehicles are expected to change drastically by the transformation of conventional liposomes into novel types such as stealth liposome, targeted liposome, and theranostic liposome. The latter is an assemblage of the previous three forms of liposomes, encompassing medicinal, imaging, and targeting molecules. The active molecule can be encapsulated in the liposome after (active approach) or during (passive approach) its formation through procedures like thin layer hydration, mechanical agitation, solvent evaporation, solvent injection, solvent dispersion, detergent removal method, and the surfactant solubilization (Eloy et al. 2014).

Accumulation of lipid vesicles at the desired location is a prerequisite for the release and absorption of the encapsulated drug besides enhanced bioavailability. The EPR effect originate passive targeting and many approved nanoliposomal formulations (e.g. Doxil®, Lipodox®_, DaunoXome®, Onivyde®, etc.) have successfully increased distribution to the diseased states based on this strategy (Caster et al. 2017). However, nanoliposomes can be synthesized by incorporating antibodies, ligands, etc. on their surface for targeted and extended delivery of drugs to organs or tissues, so that the therapeutic effect is obtained only on diseased cells sparing the normal cells. Stimuli‐responsive liposomes (pH‐sensitive, temperature‐sensitive, etc.) are also persuaded by utilizing lipids of differing fatty acid chain lengths. This allows the controlled release of their contents only on exposure to specific environmental conditions. The use of liposomal nanoformulations for drug delivery has had a major effect on anticancer, antifungal, analgesic pharmacology and is increasingly advancing to other categories as well (Patra et al. 2018).

Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are utilized for medicinal intention especially to target cancer and the transmission of ocular medicines. SLNs are biodegradable and biocompatible nanoscale colloidal carriers with a size range of 50–1000 nm. They are one of the nanocarrier systems to provide a highly lipophilic lipid matrix for dissolved and dispersed drugs manufactured by dispersing melted solid lipids in aqueous media or water using emulsifiers as a stabilizer. As carriers, SLNs deliver various advantages like higher drug payload, negligible in vivo toxicity, better bioavailability and stability of poorly soluble medicines and ease of large‐scale processing than liposomes and other colloidal systems (Vanza et al. 2020). They provide a biological medium to encapsulate lipotropic cytotoxic drugs in the core, shell, or lipid matrix and can be functionalized using compounds like oligosaccharides, proteins, antibodies, or ligands for receptors. Nevertheless, they suffer from certain restrictions that comprise of high water content required to disperse, drug leakage, and low loading capacities. The above‐stated problems related to SLNs can be overcome by using second‐generation carriers NLCs. It comprises of two main components: one is a nanostructured solid lipid matrix (a combination of liquid and solid lipids) and another is an aqueous phase (containing surfactant). In contrast to SLNs, they facilitate elevated encapsulation of active molecules, give marginal drug leakage, exalted stability and versatility (Shidhaye et al. 2008). A wide range of solid lipids are commonly used in the formulation of lipid NPs, including free fatty acids, fatty alcohols, steroids, waxes as well as monoglycerides, diglycerides, and triglycerides. In addition, oleic acid, isopropyl myristate, vitamin E, Transcutol P, Labrafac PG, Miglyol 812 N are some of the examples of liquid lipids used to manufacture lipidic nanoparticle by any of the methods, namely microemusification, high‐pressure homogenization, solvent emulsification‐evaporation technique, solvent emulsification‐diffusion technique, high shear homogenization or ultrasonication technique, solvent injection (or solvent displacement) technique, phase inversion temperature (PIT) method, and double emulsion technique (Utreja et al. 2020).

Polymer NPs are commonly used in nanomedical research for the delivery of various drugs. They are quickly synthesized and there is a vast volume of evidence on their effectiveness and protection. They provide many benefits over other delivery systems in terms of stability in the gastrointestinal atmosphere and the potential to shield encapsulated agents from drug efflux pumps and enzymatic degradation. They are considered promising carriers for a variety of drugs, including cancer, coronary disease, and diabetes treatments; bone‐strengthening treatments; and vaccines (Wibowo et al. 2020). Implementation of different polymers to produce NPs enables simple manipulation of their properties such as surface load, hydrophilicity and particle size, along with stimulus‐oriented regulated release of drugs. It is possible to change the surface of NPs by conjugating polymers with peptides and antibodies (Rahman et al. 2012). Biodegradable polymers that can be completely metabolized and eliminated from the body are of special interest in nanocarriers for drug delivery. Polymeric NPs are typically made up of polymers such as chitosan, sodium alginate, polylactic acid, poly (lactic‐co‐glycolic acid) (PLGA) and poly(ш‐caprolactone) (Chavan et al. 2020).

Nanospheres are spherical polymeric matrix particles that are rigid with drug encapsulated or dispersed within the polymer matrix. Nanocapsules are vesicular reservoir polymeric structures that act as a reservoir in which the drug is spread or absorbed in a liquid core (oil/water) surrounded by a polymer (Allen et al. 2019). Dendrimers are another form of polymeric NPs that has a branched three‐dimensional structure with ease of surface adjustment and flexibility. Various properties of dendrimers, such as high degrees of branching, size uniformity, water solubility, and the inclusion of several internal cavities, make them an effective drug delivery platform. They demonstrate the ability to enhance the solubility and bioavailability of hydrophobic drugs that may be stuck in their intramolecular cavity or conjugated to their functional surface groups. These almost monodispersed technologies represent new drug delivery systems for the treatment of various diseases and conditions of the human body. A recent emerging field of therapeutic use is the synthesis of dendrimers with bioactive ligands to promote targeted delivery and improve the effectiveness of medications with the smart use of advanced pharmaceuticals and nanomedicine. However further studies are necessary to reveal the complex structure–functional relationship of ligand–dendrimer conjugates in drug delivery processes (Lombardo et al. 2019).

Hydrophobic core–hydrophilic shell structures formed by self‐assembly of amphiphilic block copolymers in the aqueous solution are nanodrugs comprising polymeric micelles. They are investigated for the delivery of various drugs (like anti‐infective, anticancer molecules), genetic material (DNA and siRNA), proteins, peptides, etc. The micelles prepared by thin‐film hydration, sonication, or dialysis technique can be tweaked to obtain various particle sizes (20–200 nm) with narrow size distribution, drug loading and release characteristics. They can be personalized to obtain slow controlled release circumventing prompt renal clearance, thereby allowing sustained circulation and accumulation due to the impact of EPR. They flaunt biocompatibility and stability attributable to numerous amphiphilic copolymers used like poly (vinyl alcohol) (PVA), poly(ethylenimine) (PEI), poly(ε‐caprolactone) (PCL), poly‐N‐(2‐hydroxypropyl) methacrylamide (HPMA), poly(D,L‐lactic acid) (PLA), dextran, poly(D,L‐lactic‐co‐glycolic acid) (PLGA), alongside additional stealth effect offered by most widely used PEG (Utreja et al. 2020). The amphiphilic character allows poorly water‐soluble drugs to be loaded in the core with the shell providing aqueous solubility, colloidal stability, and essential stealth character. Although these nanoformulations offer improved penetrability, solubility, bioavailability, targeting through directing ligand complexed on the surface or combining monoclonal antibodies to the micelle corona, they suffer from poor in vivo stability. This effect is due to dissociation and early drug release below critical micelle concentration succeeding its administration that can also lead to drug‐related toxicity. However, stimuli‐responsive cross‐linked micelles have exhibited micellar stability and have attracted formulation scientists for the delivery of docetaxel, camptothecin, paclitaxel, cisplatin, and oxaliplatin (Ventola 2017).

The original milled organic nanocrystal, Rapamune®, approved by FDA in 2000 opened new avenues for resourceful NPs that were capable of enhancing solubility and bioavailability. Nanocrystal‐based drugs within the range of 1000 nm are peculiar because they are solely composed of drug derivatives without any carriers bound to them and are typically stabilized using polymeric steric stabilizers or surfactants. The poorly soluble organic or inorganic drugs are rendered enriched pharmacokinetic (PK)/pharmacodynamic (PD) properties by nanostructures known as nanocrystals. Nanocrystals have unique characteristics that allow them to solve problems such as increasing solubility of saturation, increased speed of dissolution, and enhanced surface/cell membrane binding. Saturation solubility increases the forces that, via biological mechanisms, such as the walls of the gastrointestinal tract, drive diffusion‐based mass transfer (Farjadian et al. 2019). The oral absorption process for nanocrystal formulations, however, is not well known and their action is not completely predictable after subcutaneous injection. They are photochemically stable and exhibit a narrow, controllable, symmetric emission spectrum. They consist of an optically energetic core enclosed by a shield that creates a physical barrier to the external environment, rendering them less vulnerable to photo‐oxidation or medium shifts. The methods of preparation of nanocrystals can be divided into top‐down and bottom‐up processes. The bottom‐up method creates nanocrystals from the solution, which requires two basic stages: nucleation and crystal formation. It mainly involves high‐pressure homogenization accompanied by grinding procedures. The top‐down methodologies comprise of high‐energy mechanical powers like milling (NanoCrystals®) or high‐pressure homogenization (IDD‐P®, DissoCubes® and Nanopure®), and the main benefit is that it is adaptable to the manufacturing scale (Lopalco and Denora 2018). Nevertheless, high energy, cost, and time used as well as impurity from grinding media are a downside of this technology, leading to unintended toxic undesirable results. Supercritical fluid (SCF) such as supercritical carbon dioxide exhibits superior physical characteristics, liquid solubilization, diffusivity similar to gas and minimal environmental effect. Thus, nanocrystals are lately prepared using SCF.

Inorganic nanocarriers have recently been used to create powerful nanocarriers for drug delivery applications attributable to easy alteration, high drug loading capability, and stability. A significant variety of inorganic materials can be used to produce NPs, such as silica, metal oxide, or metal. In particular, NPs of metal and metal oxide are being intensively studied for simultaneous therapeutic as well as imaging purposes. They are used and developed for an investigative picture of the diseased area because of the special magnetic and plasmonic properties. However, only a few inorganic NPs have been approved for clinical use, although others are still in the clinical testing stage. They are composed of a core containing the inorganic portion such as silica, gold, iron oxide, or quantum dots. A shell region consisting mostly of organic polymers (or metals) offers an adequate surface functionalization substrate or a way to protect from redundant physicochemical interactions with the biological microenvironment. Particle modification is usually done to strengthen the interaction with the biological membranes. In spite of these benefits, however, inorganic NPs have demonstrated only modest effectiveness in the treatment of disease tissues due to the crucial problems associated with the limited quantity of drug substances delivered and extreme toxicity (Lombardo et al. 2019). Gold NPs, silver NPs, and iron oxide NPs have been extensively studied in the biomedical field due to their special biochemical properties and high electron conductivity. With the approval of Abraxane® in 2005, which incorporates 130‐nm albumin NPs conjugated with paclitaxel, a shift occurred from the use of unmodified proteins to engineered particle complexes originated to enable active targeting. Protein‐based NPs include protein‐conjugated medications, formulations where the protein itself is the active therapy, and complex combined platforms that utilize proteins for targeted delivery. Generally, natural proteins are preferred to reduce toxicity. In the last decade, albumin has gained the attention of research scientists as a drug carrier due to the facilitation of cellular uptake mechanisms and accumulation via EPR effect (Ventola 2017). Mesoporous silica NPs, quantum dots, and carbon nanotubes have also registered their applications in biomedical and nanomedicine fields. Moreover, nanocarriers that are equipped with complex surface functionalization of inorganic nanocarriers with organic materials or through the use of organic colloids as a template for the regulated growth of inorganic materials have recently attracted considerable global interest. For example, surface coating of mesoporous silica NPs with polyethyleneimine improves cellular uptake and enables siRNA and DNA constructs to be transported safely (Paris and Vallet‐Regí 2020). Lately, lipid‐coated mesoporous silica NPs have also been employed to achieve stimuli‐responsive drug release, promote drug loading, prevent premature release of drug, avoid multidrug resistance, stability, and biocompatibility.