Nanoparticles in Drug Delivery: From History to Therapeutic Applications

Current research into the role of engineered nanoparticles in drug delivery systems (DDSs) for medical purposes has developed numerous fascinating nanocarriers. This paper reviews the various conventionally used and current used carriage system to deliver drugs. Due to numerous drawbacks of conventional DDSs, nanocarriers have gained immense interest. Nanocarriers like polymeric nanoparticles, mesoporous nanoparticles, nanomaterials, carbon nanotubes, dendrimers, liposomes, metallic nanoparticles, nanomedicine, and engineered nanomaterials are used as carriage systems for targeted delivery at specific sites of affected areas in the body. Nanomedicine has rapidly grown to treat certain diseases like brain cancer, lung cancer, breast cancer, cardiovascular diseases, and many others. These nanomedicines can improve drug bioavailability and drug absorption time, reduce release time, eliminate drug aggregation, and enhance drug solubility in the blood. Nanomedicine has introduced a new era for drug carriage by refining the therapeutic directories of the energetic pharmaceutical elements engineered within nanoparticles. In this context, the vital information on engineered nanoparticles was reviewed and conferred towards the role in drug carriage systems to treat many ailments. All these nanocarriers were tested in vitro and in vivo. In the coming years, nanomedicines can improve human health more effectively by adding more advanced techniques into the drug delivery system.


Introduction
Drug delivery systems (DDSs) have been used in past eras to treat numerous ailments. All medicines rely on pharmacologic active metabolites (drugs) to treat diseases [1]. Some of the drugs are designed as the inactive precursor, but they become active when transformed in the body [2]. Their effectiveness depends on the route of administration. In conventional drug delivery systems (CDDSs), drugs were delivered usually via oral, nasal, inhaled, mucosal, and shot methods [3]. The conventionally delivered drugs were absorbed less, distributed randomly, damaged unaffected areas, were excreted early, and took a prolonged time to cure the disease [4]. They were less effective due to many hurdles like their enzymatic degradation or disparity in pH, many mucosal barriers, and off-the-mark effects, and their immediate release enhanced toxicity in blood [5].
Due to all such reasons, the controlled-release drug delivery system was developed. Such evolution in the DDS enhances drug effectiveness in many ways [6]. DDSs have been Figure 1. Illustration of how traditional medications were administered without the use of nanocarriers and harm was done to healthy organs or cells. In contrast, modern procedures use nanomedicines to transport medications to specific parts of the body.
In 1959, Feynman was the first physicist to introduce the notion of nanotechnology in the lecture entitled "There's Plenty of oom at the Bottom". This concept initiated remarkable developments in the arena of nanotechnology [15]. Nanotechnology is the study of extremely tiny things and is basically the hub of all science disciplines including physics, chemistry, biology, engineering, information technology, electronics, and material science [16]. The structures measured with nanotechnology range from 1-100 nm at the nanoscale level [17]. Nanoparticles have different material characteristics because of submicroscopic size and also provide practical implementations in a wide range of fields includ- Figure 1. Illustration of how traditional medications were administered without the use of nanocarriers and harm was done to healthy organs or cells. In contrast, modern procedures use nanomedicines to transport medications to specific parts of the body.
In 1959, Feynman was the first physicist to introduce the notion of nanotechnology in the lecture entitled "There's Plenty of oom at the Bottom". This concept initiated remarkable developments in the arena of nanotechnology [15]. Nanotechnology is the study of extremely tiny things and is basically the hub of all science disciplines including physics, chemistry, biology, engineering, information technology, electronics, and material science [16]. The structures measured with nanotechnology range from 1-100 nm at the nanoscale level [17]. Nanoparticles have different material characteristics because of submicroscopic size and also provide practical implementations in a wide range of fields including engineering, drug delivery, nanomedicine, environmental indemnification, and catalysis, as well as target diseases such as melanoma and cardiovascular diseases (CVD), skin diseases, liver diseases, and many others [18].
Therefore, medicines linked with nanotechnology can enhance efficiency of medicines and their bioavailability [19]. The relation of nanoparticles to biomedicine was demonstrated in late the 1970s, and over 10,000 publications have referred to this association with the term "nanomedicine". Almost thirty papers on this term were accessible by 2005 [20].
After 10 to 12 years, Web of Science published more than 1000 nanomedicine articles in 2015 and most of the articles relating nanoparticles (NPs) for biomedical usage [21]. Nanocarriers such as dendrimers, liposomes, peptide-based nanoparticles, carbon nano tubes, quantum dots, polymer-based nanoparticles, inorganic vectors, lipid-based nanoparticles, hybrid NPs, and metal nanoparticles are the advanced forms of NPs [22]. Nanoparticles are nowadays a growing arena for drug delivery, microfluidics, biosensors, microarrays, and tissue micro-engineering for the specialized treatment of diseases [23][24][25].
Nanoparticles are less effective and can treat cancer by selectively killing all cancerous cells [26]. In 2015, the Food and Drug Administration (FDA) approved the clinical trials of onivyde nanomedicine in the treatment of cancer [27]. The characteristic properties of nanocarriers are physicochemical properties, supporting the drugs by improving solubility, degradation, clearance, targeting, theranostics, and combination therapy [28]. Studies on nanomedicine based on protein used for drug delivery in which various protein subunits combine to deliver medicine on site to a specific tumor have been reported [29]. Many altered kinds and forms of nanocarriers arranged to carry medicine are protein-based podiums, counting several protein coops, nanoparticles, hydrogels, films, microspheres, tiny rods, and minipellets [30]. All proteins, including ferritin-protein coop, the small heat shock protein (sHsp) cage, plant-derived viral capsids, albumin, soy and whey protein, collagen, and gelatin-implemented proteins are characterized for drug carriage [31].
The nanomedicines are escorted in a new-fangled epoch, meant for drug carriage by refining the therapeutic directories of the energetic pharmacological elements engineered inside nanoparticles [32]. In this epoch, nanomedicine-based targeted-design structures can deliver multipurpose freight with favorable pharmacokinetics and capitalized so as to enhance drug specificity, usefulness, and safety, as shown in (Figure 2) [33]. The failure of chemotherapeutic approaches has increased the recurrence chances of disease, which enhances the complexity of lethal diseases [34].

History
Petros and his colleague reported a study about mid-19th century work on nanotechnology. As they reported, polymers and drugs were conjugated in 1955 [35], the first controlled-release polymer device appeared in 1964, the liposome was discovered by Bangham in 1965, albumin-based NPs were reported in 1972, liposome-based drugs were formulated in 1973, the first micelle was formulated and approved in 1983, the FDA approved the first controlled formulation in 1989, and first polyethylene glycol (PEG) conjugated with protein entered the market in 1990 [36]. Further studies have produced incredibly encouraging results for treating a variety of disorders (Table 1).

Figure 2.
Aids of using nanomedicine platform for delivering drugs to the tumor complex.

History
Petros and his colleague reported a study about mid-19th century work on nanotechnology. As they reported, polymers and drugs were conjugated in 1955 [35], the first controlled-release polymer device appeared in 1964, the liposome was discovered by Bangham in 1965, albumin-based NPs were reported in 1972, liposome-based drugs were formulated in 1973, the first micelle was formulated and approved in 1983, the FDA approved the first controlled formulation in 1989, and first polyethylene glycol (PEG) conjugated with protein entered the market in 1990 [36]. Further studies have produced incredibly encouraging results for treating a variety of disorders (Table 1). Scanning electron microscope (SEM) [37,38] 1992 Calcium hydroxyapatite ceramic (CHC) Drug gentamicin placed in the porous blocks of calcium hydroxyapatite antibiotics (CHA).
Chronic osteomyelitis (animal model) The bactericidal activity was retained and drug shows effective results.
No in vivo experiments performed [39,40] 1993 Nano and micro particles Micro-particulate system used for the administration of the drug. Enhance oral immune system (immunization) In vitro, self-diffusion, liberation due to erosion, pulsed delivery due to oscillating field.
In vitro experiments performed [41,42] 1994 Acrylic acid copolymer NPs Acrylic acid, acrylic amide, acrylic-butyl ester, and methacrylic methyl ester used as copolymer in drug delivery.

No
Help opsonin to reach specific target site and also enhance reticuloendothelial system. Small angle X-ray scattering [43,44] 1995 Poly-alkyl-cyanoacrylate (PECA) nanoparticles Ofloxacin (OFX) and perfloxacine entrapped in PECA nanoparticles. OFX system more efficient than PFX system.

Bacterial diseases
The fluoro-quinolone-loaded nanoparticles enhance antimicrobial activity of the drug.

Protein and peptides-based NPs
Monoclonal antibodies, recombinant proteins transported to BBB by chimeric peptide approach.
Alzheimer's disease Avidin conjugate with BBB vector to transport all proteins across BBB. Vasoactive intestinal peptide cures brain diseases.
No characterization of physiologic-based strategy [47,48] 1997 Nanoparticle Nanoparticles as carrier to deliver drug to intra-arterial localization system. Cather based delivery

Restenosis (arterial reobstruction)
Easily penetrate into the arterial wall and without causing injury. Biocompatible and effective for restenosis treatment.

Diblock copolymer nanoparticles
Micelles and nanosphere carry genes and hydrophobic drugs to target site. No Help to sustain drug rate. Solubilize, release, and protect drugs. Enhance retention time in the blood.
No [51,52] 1999 Chitosan nanoparticles Potential of chitosan nanoparticles to improve absorption of insulin through nasal cavity. Diabetes MicroAB assay used to determine insulin loading and release.
Zeta potential, laser doppler anemometry, photon correlation spectroscopy [53,54]  Folate-associated, lipid-based nanoparticles transport DNA with high transfection efficacy and constraining tumor progress with intratumoral shot into human nasopharyngeal and prostate malignancy using an HSV-tk/GCV treatment system.
No [65,66]  AFM and zeta potential, UV Spectro-photometer characterize particle size determination [67,68] 2007 Gold nanoparticles (AuNPs) Drug and gene delivery approach to deliver drugs and genes by using gold nanoparticles. The transfection efficacy for beta galactosidase with various MMPCs.

Human nasopharyngeal carcinoma
Properties of drug transfer like reduced toxicity, treating acute diseases, uptake and release rate using fluorophore AuNPs provide added insight in future.

PEGylated gold nanoparticles
Very effective drug transfers with AuNPs' vector for in vivo photodynamic treatment in cancer.

Cancer
The diversity in medicine released in vitro in two-phase solution system. In vivo in cancer-bearing mice shows that the way of drug carriage is enormously well-planned, and submissive targeting prefers the tumor area.
TEM and image analysis, DLS measurement, UV-vis, and fluorescent spectrophotometer [71,72] 2009 Alginate/ Chitosan (Alg/Chi) nanoparticles Nanoparticles of alginate/chitosan polymers were arranged by pre-gel preparation method via drop-wise addition of several concentrations of CaCl 2 to a definite concentration of sodium alginate.

No
Optimization of Alg/Chi NPs and preparation are areas of this research. Some parameters like ratio of Alg/Chi, ratio of CaCl 2 /Alginate and N/P can disturb size and loading ability of these particles.

Mesoporous silica nanoparticles
Targeted carriage of chemotherapeutic mediator methotrexate (MTX) to tumor cells by means of poly (ethylene mine)-functionalized mesoporous silica small units as vectors for drug delivery. Scanning electron microscope (SEM) [75,76] 2011 Nano diamond (ND) or diamond nanoparticles Nano diamonds have ability to transport small interfering RNA into sarcoma (Ewing) cells.
Was examined with evaluation of the route of in vivo anticancer nucleic acid drug transfer.

Ewing Sarcoma Cells (Cancer)
Well-organized delivery of oligonucleotide by a cationic nano-diamond nanoparticle: (i) Suitably robust adsorption of the biomolecule on the particle surface across the cell membrane deprived of damage of material; (ii) The severance of the compound on the time-scale of a cell division cycle.
FT-IR confirm the absorption of PAH on nano-diamonds and zeta potential [77,78] 2012

Silver nanoparticles
This method was to design stable silver NP vector to make larvicides of mosquitos to destroy mosquitos' life with drugs.

Malaria, Dengue fever, Filariasis
The leaf potage of Annona squamosa used as an active capping and reducing mediator for the fusion of silver nanoparticles.
Ultraviolet spectrophotometry, X-Ray diffraction, FT-IR, SEM [79,80] 2013 Silver nanoparticle Nanoparticles of noble metal show potential as photo-activated vectors for drug delivery. SNPs conjugated with thiol-terminated photo-liable DNA oligonucleotides.

Photo-activated gene silencing
Good consistency to nucleases, hybridization amplified action upon photo release, and effective cellular uptake as associated to commercial transfection vectors.
UV-spectrophotometer, fluorescent confocal microscopy [81,82] 2014 Silver nanoparticles as drug-loading vector Silver nanoparticles synthesized from plant Pongamia pinnata by green method. Dengue Medically active plant and earth eco-friendly. Larvicidal action of silver nanoparticles and leaf extract contrary to Aedes aegypti showed positive results.

Polyamidoamine nanoparticles
Polyamidoamine nanoparticles work as nanocarrier and deliver anti-malarial drug to the targeted sites. It also works as nanomedicine.

Malaria
Union of doxorubicin and polymers increases drug solubility, enhances its blood half-life, decreases toxicity, and enhances targeting.
Colon cancer Drug transfer potential of therapeutics compressed with electroporation.

Filamentous bacteriophage and phage-mimetic nanoparticles
Delivery of drug and gene through phage particles. Phage can be chemically altered or genetically designed to load drugs and transfer foreign genes.

Bacterial and viral diseases
Filamentous bacteriophage used in the making of mark medicine transfer as virus-based delivery system. The bacteriophage uncovered with mark-definite peptides or antibodies can be bound with other carriers (such as liposomes, inorganic NPs) to make a unique transfer scheme.

No
The practice of non-viral vectors can solve most of these problems like short time, noxiousness while inorganic, and non-viral vectors, like MSNs, are also very affordable and vigorous.

Chitosan nanoparticles
Drug loaded on chitosan nanoparticles to deliver to targeting sites. All types of drug delivery sites involved.

No
Ocular drug delivery, vaccine delivery, perioral delivery, vaccine transfer, mucosal and nasal drug transfer, gene carriage, pulmonary drug delivery, buccal medicine distribution, vaccine transfer, and cancer treatment.
No [93,94] 2020 Mesoporous silica NPs with folic acid (MSN−COOH-Tet-HBP-FA) This approach is pH subtle drug delivery system built on folic-acid-targeted HBP to re-form/reshape the mesoporous silica nanoparticles.

Cancer
The hyper-branched polymer HBP encapsulates the drug particles in the mesopores as a lid, which progresses the permanency of the carrier material and permits the drug to attain "zero pre-release" within 20 h in a usual physiological atmosphere.
XRD, TEM, HNMR spectra, SEM, UV-analysis, Thermogravimetric analysis (TGA) [95,96] 2021 Novel silver nanoparticles In this approach, DNA or messenger RNA (mRNA) sequences are transported to the body to produce proteins, which copy disease antigens to arouse the immune response.

SARS-CoV-2
The nucleic acid vaccines comprise cell-mediated and humoral immunity activation, affluence of strategy, quick malleability to altering pathogen strains, and customizable multi-antigen vaccines.
To fight the SARS-CoV-2 epidemic and many other ailments, nucleic acid vaccines seem to be a hopeful way.

Brain Drug Delivery System and Its Types
Under the most pathological circumstances of diseases such as strokes, seizures, multiple sclerosis, AIDS, diabetes, glioma, Alzheimer's disease, and Parkinson's disease, the blood-brain barrier (BBB) is disrupted [103]. An important reason for the breakdown of the blood-brain barrier is the remodeling of the protein complex in intra-endothelial junctions under the pathological conditions [104]. Normally, the blood-brain barrier acts to maintain blood-brain homeostasis by preventing entry of macromolecules and micromolecules from the blood [105]. If a drug crosses the BBB, it restricts accumulation of the drug in the intracerebral region of brain, and bioavailability is reduced, due to which brain diseases cannot be treated [106]. Therefore, the optimal drug delivery system (DDS) is a cell membrane DDS, virus-based DDS, or exosome-based DDS designed for BBB penetrability, lesion-targeting ability, and standard safety [107]. For the cure of brain diseases, the nanocarrier-assisted intranasal drug carriage system is widely used [108]. Now, at the advanced level, drugs poorly distributed to the brain can be loaded into a nanocarrier-based system, which would interact well with the endothelial micro vessel cells at the BBB and nasal mucosa to increase drug absorption time and the olfactory nerve fibers to stimulate straight nose-to-brain delivery [109], thus greater drug absorption in brain parenchyma through the secondary nose-to-blood-to-brain pathway [110]. The current strategies used are viral vectors, nanoparticles, exosomes, brain permeability enhancers, delivery through active transporters in the BBB, alteration of administration route, nanoparticles for the brain, and imaging/diagnostics under diseased conditions [111].

Role of Nanocarriers in Alzheimer's Disease
Alzheimer's disease is one of the fastest growing neurodegenerative diseases in the elderly population. Clinically, it is categorized by abstraction, damage to verbal access, and diminishing in spatial skills and reasoning [112]. Furthermore, engrossment of amyloid β (Aβ) aggregation and anxiety in the brain have significant parts [113]. The treatment of different diseases with nanotechnology-based drug delivery uses nanotechnology-based approaches [114]. In Alzheimer's diseases, polymeric nanoparticles, liposomes, solid lipid nanoparticles, nano-emulsions, micro-emulsions, and liquid-crystals are used for treatment.
Polymeric Nanoparticles I.
The drug Tacrine was loaded on polymeric nanoparticles and administered through an intravenous route. It enhanced the concentration of tacrine inside the brain and also reduced the whole-dose quantity [115]. II. Rivastigmine drug was loaded on polymeric nanoparticles and administered through an intravenous route. It enhanced learning and memory capacities [116].

Solid Lipid Nanoparticles (SLNPs)
SLNPs enhanced drug retention in the brain area, raising absorption across the BBB [117]. Some of the drug's effects are listed below.

I.
Piperine drug is loaded on solid lipid nanoparticles through an intraperitoneal route inside the brain to decrease plaques and masses and to increase AChE enzyme activity [118]. II. Huperzine A improved cognitive functions. No main irritation was detected in rat skin when the drug was loaded on SLNPs in an in vitro study [119].
In recent reports, the coating of SLNPs with polysorbate enhances drug bioavailability [120,121]. Some of the coated NPs are listed below.

I.
The drug clozapine was loaded on a Dynasan 116 [Tripalmitin] lipid matrix coated with surfactant Poloxamer 188, Epikuron 200 to unload the drug safely into the brain microenvironment [122,123].  [124,125]. III. Diminazine was loaded on a stearic acid matrix coated with polysorbate 80 to deliver to an infected area safely [126,127]. IV. Doxorubicin was loaded on stearic acid SLNs coated with Taurodeoxycholate surfactant to deliver the drug without reducing its effectiveness [128,129].

Liposomes
Liposomes have gained attention as auspicious tactics for brain-targeted drug delivery [130]. The recorded beneficial features of liposomes are their capacity to integrate and carry a large quantity of drugs and their likelihood to adorn their exterior with diverse ligands [131,132].

•
Curcumin-PEG derivative was loaded on liposomes and showed high affinity on senile plaques in an ex vivo experiment. Furthermore, in vitro it demonstrated the ability for Aβ aggregation and was taken inside by the BBB in a rat model [133].

•
Folic acid was loaded on liposomes, administered through an intranasal route and absorbed through the nasal cavity [134].

I.
Tacrine was loaded on a microemulsion and improved memory. Such nanoparticles absorbed rapidly via the nose to the brain through an intranasal route [135].

I.
T. divaricate was loaded on liquid crystals and injected through a transdermal route. It increased permanency of the drug in designs and also increased skin infusion and retention [136].

Role of Nanocarriers in Parkinson's Disease (PD)
Parkinson's disease is considered the second most common neurological ailment, and it faces problems in reliable drug delivery for treatment and diagnosis [137]. The conventional anti-Parkinson's drug is Levodopa, but it experiences low bioavailability and deprived transfer to the brain; this is the most thought-provoking problem [138]. To solve this problem, nanotechnology comes to the fore with insightful solutions to solve this problem. Various nanoparticles like metal nanoparticles, quantum dots, cerium oxide nanoparticles, organic nanoparticles, liposomes, and gene therapy are used in PD treatment [139]. All these nanoparticles enable drugs to enter through numerous ways across the blood-brain barrier (BBB) [140]. In the current study, Bhattamisra et al. reported Rotigotine drug loaded on chitosan NPs in human SH-SY5Y neuroblastoma cells and delivered from the nose to the brain in rat model of Parkinson's disease. A study of the pharmacokinetic data proposed that the intranasal route is the best path for a straight channel of rotigotine to the brain [125].

Ropinirole (RP)
Ropinirole (RP) is a dopamine agonist used for Parkinson's treatment. RP-loaded solid lipid nanoparticles (RP-SLNs) with nanostructured lipid carriers (RP-NLCs) comprising hydrogel (RP-SLN-C and RP-NLC-C) formulations are better for oral and topical distribution [141]. Generally, the results confirmed that lipid nanoparticles and consistent hydrogel formulations can be measured as another carriage methodology for the upgraded oral and topical delivery of RP for the active treatment of PD [142]. Neurodegenerative pathologies such as AD and PD can be treated with solid lipid nanoparticles, as this permits the drug to cross the BBB and reach the damaged area of the central nervous system [143].

Mechanism of Nanoparticles' Brain Drug Delivery (across BBB)
The NPs are commonly administered via intranasal, intraventricular, intraparenchymal routes. All these routes enabled nanoparticles to cross the BBB due to their small size. When nanoparticles reach the BBB, several mechanisms are used, like receptor-mediated mechanisms, active transport, and passive transport to deliver nanoparticles into the brain. Nanoparticles are small in size, can diffuse passively across the endothelial cells of the BBB, and can interact favorably with brain receptors and recognize ligands for interaction ( Figure 3) [144].
distribution [141]. Generally, the results confirmed that lipid nanoparticles and consistent hydrogel formulations can be measured as another carriage methodology for the upgraded oral and topical delivery of RP for the active treatment of PD [142]. Neurodegenerative pathologies such as AD and PD can be treated with solid lipid nanoparticles, as this permits the drug to cross the BBB and reach the damaged area of the central nervous system [143].

Mechanism of Nanoparticles' Brain Drug Delivery (across BBB)
The NPs are commonly administered via intranasal, intraventricular, intraparenchymal routes. All these routes enabled nanoparticles to cross the BBB due to their small size. When nanoparticles reach the BBB, several mechanisms are used, like receptor-mediated mechanisms, active transport, and passive transport to deliver nanoparticles into the brain. Nanoparticles are small in size, can diffuse passively across the endothelial cells of the BBB, and can interact favorably with brain receptors and recognize ligands for interaction ( Figure 3) [144]. Diagram showing the mechanism of targeted drug delivery across BBB in brain microenvironment. Piperine loaded on SLNPs is injected intraperitonially, across BBB efferently to stop plaque formation. Polymeric nanoparticles are used for Tacrine delivery inside the brain, folic acid are loaded on the liposomes crossing blood-brain barrier to treat Alzheimer's disease, while nanoemulsions and SLNP are loaded with drugs used to deliver medicines inside the targeted brain area to cure Parkinson's disease.

Advantages and Disadvantages of Nanomedicines
When employed for brain illnesses, nanomedicines have both benefits and drawbacks (Table 2). Diagram showing the mechanism of targeted drug delivery across BBB in brain microenvironment. Piperine loaded on SLNPs is injected intraperitonially, across BBB efferently to stop plaque formation. Polymeric nanoparticles are used for Tacrine delivery inside the brain, folic acid are loaded on the liposomes crossing blood-brain barrier to treat Alzheimer's disease, while nanoemulsions and SLNP are loaded with drugs used to deliver medicines inside the targeted brain area to cure Parkinson's disease.

Advantages and Disadvantages of Nanomedicines
When employed for brain illnesses, nanomedicines have both benefits and drawbacks ( Table 2). Table 2. Advantages and disadvantages of nanomedicine.

Nanomedicine Names
Advantages Disadvantages Ref.

Tacrine-loaded polymeric NPs
NPs are reserved in the brain for long time, biocompatible, low in cost, control drug release, and targeted conjugation with ligands Slowly degradable, sometimes uncertain toxicity [145] Rivastigmine-loaded polymeric NPs They increase drug concentration in the brain, avoid phagocytosis by RES Increase oxidative stress, toxicity [146] Piperine-loaded SLNPs Widely examined, fewer side effects of drugs, improved therapeutic effects and drug solubility Low loading capacity, easily cleared by reticuloendothelial system [147] Folic-acid-loaded liposomes Highly biocompatible and biodegradable, High stability and bioavailability, active surface targeted Difficulty in binding with lipids, low stability and drug carriage rate [148] Beta-Asarone-loaded nanoemulsions Improved bioavailability, capability to hydrolyze hydrophobic and hydrophilic drugs Thermodynamically unstable, instant drug release [149]

Brain Cancer
Brain malignancy is the most critical disease in the sense of treatment [150]. Malignancies of the brain are most difficult to treat due to limits imposed by the blood-brain barrier [151]. The brain microvascular endothelium is present in the BBB and creates barriers that distinguish blood from the neural tissues of the brain [152]. The BBB prevents the entry of harmful toxins, xenobiotic and other metabolites from entering the brain [153]. The majority of brain cancers include glioma and glioblastoma. Both of these are among the most lethal forms of brain cancer [154]. The annual occurrence is 5.26 per 100,000 people or 17,000 new diagnoses each year. The most common treatment is radiation surgery and chemotherapy, usually implemented with with temozolomide (TMZ) [155]. Nanoparticles have a high potential to treat brain cancer because of their small size in nm, tissue-specific targeting properties, and ease in crossing the BBB [156] (Table 3).

Breast Cancer
Cancer causes major deaths all over the world. Tumors spread due to the proliferation of cells [171], which invade through the lymphatic system to various parts of the body if they becomes malignant [172]. According to WHO, the ratio of deaths globally due to cancer is assessed to be 13%, attributing 8.2 million deaths every year [173]. Breast cancer is the most recorded type of melanoma present in only females, and its severity leads to mortality more often than lung cancer [174]. In 2012, estimated female breast cancer cases were 1.7 million, with 25% of deaths all over the world [175]. In a recent study, a report published in the name of Global Cancer Statistics 2020: GLOBOCAN estimates the incidence and mortality worldwide for 36 cancers in 185 countries and provides an update on cancer internationally [176]. A reported estimate is 19.3 million new cancer cases (18.1 million excluding non-melanoma skin cancer) and almost 10 million cancer deaths (9.9 million without non-melanoma skin cancer) occurring in 2020 worldwide. Female breast cancer has exceeded lung cancer as the most frequently diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), prostate (7.3%), colorectal (10%), and stomach (5.6%) cancers [177]. For the effective treatment of breast cancer, surgery, chemotherapy, radiation therapy, hormonal therapy, and targeted therapy are performed [178]. However, nowadays, nanotechnology has gained interest for breast cancer treatment. Various organic and inorganic nanocarriers are used to deliver drugs to the specific target site [179]. Nanocarriers enhance the hydrophobicity of the anticancer drugs and promote specific target drug delivery [180]. Organic nanocarriers include polymeric nanocarriers, liposome nanocarriers, and solid lipid nanocarriers, while inorganic nanocarriers include magnetic nanocarriers, quantum dots, and carbon nanotubes (CNTs); both categories show great results towards treatment of heart diseases (Table 4) [181]. The mechanism of drug delivery in breast cancer is shown in Figure 4. In vitro cytotoxic activity and human glioma cell lines in vivo The effectiveness of 5-FU to medicate the brain malignancy is improved when it is designed with LDC nanoparticles. Lactate dehydrogenase (LDH) and 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assays to check cell membrane damage. Caspase-3 activity and TUNEL assays were performed to confirm induced apoptosis. [182,183] Curcumin-Solid Lipid nanoparticles (CURC-SLNs) CURC-loaded SLNs and doxorubicin p-glycoprotein (Pgp)

HER2-overexpress in breast cancer
Anti-HER2-conjugated O-succinyl chitosan graft pluronic F127 copolymer nanoparticles are effective for the making of anticancer drug carriers. Gemcitabine-hydrochloride-loaded gold nanoparticles developed using gum acacia as a polysaccharides-based system. [190,191] Magnetic nanoparticles L-carnosine-coated magnetic nanoparticles (CCMNPs) L-carnosine In vitro In vivo Breast cancer CCMNPs were targeted precisely, amassed in lump, showing noteworthy decrease in lump mass size with no general harmfulness. Figure 4. Schematic representation of mechanism of drug letrozol loaded on solid lipid nanoparticles (SLNs) and folic acid coupled to SLNs. The whole carrier was delivered inside the animal rat model to treat effects on breast cancer cell lines. Inside cytoplasm, biodegradation occurred, as well as drug release and caspases' activation inside nucleus, causing apoptosis.

Lung Cancer
Lungs are basically responsible for inhalation [194]. The lung is composed airways (conveying the air inside and outside of the lungs) and alveoli (gas exchange zones) [195]. In fact, airways are comparatively tough barriers for particles to enter through, while the barrier along the alveolar wall and the capillaries is relatively fragile in the gas exchange component [196]. The huge exterior area of the alveoli and deep air blood exchange cause the alveoli to be less healthy when affected by environmental injuries. Such injuries may be the reason for some pulmonary illnesses, including lung malignancy [197]. Several nanoparticles are now being established for respiratory applications that aim at eliminating the restrictions of orthodox drugs [198] (Table 5). Nanoparticles aid the cure of many lung diseases, such as asthma, tuberculosis, emphysema, cystic fibrosis, and cancer [199]. . Schematic representation of mechanism of drug letrozol loaded on solid lipid nanoparticles (SLNs) and folic acid coupled to SLNs. The whole carrier was delivered inside the animal rat model to treat effects on breast cancer cell lines. Inside cytoplasm, biodegradation occurred, as well as drug release and caspases' activation inside nucleus, causing apoptosis.

Lung Cancer
Lungs are basically responsible for inhalation [194]. The lung is composed airways (conveying the air inside and outside of the lungs) and alveoli (gas exchange zones) [195]. In fact, airways are comparatively tough barriers for particles to enter through, while the barrier along the alveolar wall and the capillaries is relatively fragile in the gas exchange component [196]. The huge exterior area of the alveoli and deep air blood exchange cause the alveoli to be less healthy when affected by environmental injuries. Such injuries may be the reason for some pulmonary illnesses, including lung malignancy [197]. Several nanoparticles are now being established for respiratory applications that aim at eliminating the restrictions of orthodox drugs [198] (Table 5). Nanoparticles aid the cure of many lung diseases, such as asthma, tuberculosis, emphysema, cystic fibrosis, and cancer [199].

Drug Delivery Approach in Heart Diseases
Cardiovascular diseases include myocardial infraction (MI) [213], ischemic impairment, coronary artery disease (CAD), heart arrhythmias, pericardial disease, cardiomyopathy (heart muscle disease), and congenital heart disease [214,215]. All these illnesses are the basic main cause of mortality and morbidity in the world [216]. Cardiac diseases in humans involve incongruity in the morphogenesis of heart arrangement, functionality, and the healing and periodic shrinkage of cardiac muscles [217,218]. Around 50% of patients suffering from MI die within five years [216]. The insistence for a novel and effective remedy has brought about progress in direct drug carriage to the heart [219]. Modern therapeutic approaches have been developed to stop the incidence of heart failure after myocardial infarction [220]. Liposomes, silica NPs, dendrimers, cerium oxide NPs, micelles, TiO 2 NPs, stents with nano-coatings, microbubbles, and polymer-drug conjugates are used for drug delivery. Magnetic nanoparticles like magnetoliposomes (MLs) are made up of the union of liposomes and magnetic nanoparticles. They are used as magnetic-targeted drug delivery [221]. The PEGylation of MLs increases their rate of flow in the blood, and pairing of the MLs with antibodies raises the rate of active target to pretentious positions [222]. Namdari and his co-workers performed experiments in a mice model afflicted with myocardial infraction (MI). Liposomes are used with various modifications and in different ways; they are adapted to load drugs on NPs for efficient delivery inside the cell. Cationic liposomes, perfluorocarbon nanoparticles, polyelectrolyte nanoparticles, and polymeric nanoparticles are the modified forms of nanocarriers [223] (Table 6).

Drug Delivery Approach in Skin Diseases
Skin diseases are follicular and cutaneous. These dermatological diseases are treated nowadays with nanotechnology. Nanoparticle delivery for cutaneous disease treatment is preferred, with minor side effects. The conventionally used creams, gels, and ointments are insufficient for delivering drugs due to low penetration in skin tissues. To address this, polymeric, lipid, and surfactant nanocarriers are used. The polymeric micelles enhance drug penetration into the skin tissue to treat skin cancer. As in this reported study, chitosan polymeric NPs, liposomes, and gold nanoparticles can treat atopic dermatitis by improving drug penetration into the dermal and epidermal layers [246]. Gold nanoparticles are extremely small in size and can penetrate easily and effectively with very low toxicity and no skin damage. As such, they are used widely in nanocarrier formulations for skin diseases.

Drug Delivery Approach in Bone Diseases
Bone diseases includes bone defects due to many pathological factors, such as fracture, trauma, osteoporosis, arthritis, infections, and many other diseases. In fact, bone regeneration as a disease treatment is a very complex process, due to which nanomaterials and biological materials are fused to repair bones effectively. The combination of biomaterial and nanomaterial has reduced bone implantation through the development of bone bioscaffolds [247].

Mechanism of Drug Delivery
The drugs encapsulated inside the nanoparticle is delivered through blood to the targeted area in the bones. The management of the sending nanoparticles as shown herenin ( Figure 5). toxicity and no skin damage. As such, they are used widely in nanocarrier formulation for skin diseases.

Drug Delivery Approach in Bone Diseases
Bone diseases includes bone defects due to many pathological factors, such as frac ture, trauma, osteoporosis, arthritis, infections, and many other diseases. In fact, bone re generation as a disease treatment is a very complex process, due to which nanomaterial and biological materials are fused to repair bones effectively. The combination of bio material and nanomaterial has reduced bone implantation through the development o bone bioscaffolds [247].

Mechanism of Drug Delivery
The drugs encapsulated inside the nanoparticle is delivered through blood to the tar geted area in the bones. The management of the sending nanoparticles as shown hereni ( Figure 5).

Drug Delivery Approach in Blood Diseases
There are various types of blood diseases, like hemopoietic blood disorder, as well a iron deficiency, leukemia, anemia, hemophilia, platelet diseases, and blood cancer. Th conventionally used chemotherapeutic system causes damage to the immune system with high risk of mortality. Bone marrow transplant is also an expensive and intricat process. For example, thalassemia is treated with deferoxamine, a chelating agent to trea excessive iron in the blood. The siRNA-coated nanocomposite has the inhibitory activit for tumor cells in vivo [248]. The treatment of blood disorders with nanomedicine is sti under investigation.

Future Challenges of Nanomedicines
In the field of nanomedicine, there are many innovations which show its importanc in clinical and other medical aspects. Many scientists have investigated in their researc how nanomedicine is involved in treating malignancies and reducing mortality and mor bidity rates. However, there are also future challenges that nanomedicines have been fac ing until now [249]. The implementation of nanomedicine in clinical practice will fac many issues with insurance companies, regulatory agencies, and the public health secto Until now, the FDA has not developed any specific regulation for the products containin

Drug Delivery Approach in Blood Diseases
There are various types of blood diseases, like hemopoietic blood disorder, as well as iron deficiency, leukemia, anemia, hemophilia, platelet diseases, and blood cancer. The conventionally used chemotherapeutic system causes damage to the immune system, with high risk of mortality. Bone marrow transplant is also an expensive and intricate process. For example, thalassemia is treated with deferoxamine, a chelating agent to treat excessive iron in the blood. The siRNA-coated nanocomposite has the inhibitory activity for tumor cells in vivo [248]. The treatment of blood disorders with nanomedicine is still under investigation.

Future Challenges of Nanomedicines
In the field of nanomedicine, there are many innovations which show its importance in clinical and other medical aspects. Many scientists have investigated in their research how nanomedicine is involved in treating malignancies and reducing mortality and morbidity rates. However, there are also future challenges that nanomedicines have been facing until now [249]. The implementation of nanomedicine in clinical practice will face many issues with insurance companies, regulatory agencies, and the public health sector. Until now, the FDA has not developed any specific regulation for the products containing nanomaterials. Due to a lack of nanomaterial standardization and other safety issues, US agencies, such as the EPA and NIOSH, are giving less funding to these research endeavors.

Conclusions
Nanotechnology-based nanomedicine is a diverse field for disease treatment. Nowadays, in every sort of disease, nanotechnology is emerging as the best therapeutic to cure disease. At California University, researchers are developing methods to deliver cardiac stem cells to the heart. They attached nanovesicles that directly target injured tissue to increase the amount of stem cells there. Thus, the involvement of stem cells with nanotechnology will develop many solutions for the disease-based queries in the medical arena. However, nanomedicine and nano drugs deal with many doubts. Irregularities and toxicity and safety valuations will be the topic of development in the future. Nanotechnology will be in high demand. Nowadays, drug-targeted delivery through nanoparticles is catching the attention of pharmaceutical researchers all over the world. Nanomedicine will overcome all the side effects of traditional medicines. This nanoscale technology will be incorporated in the medical system to diagnose, transport therapeutic drugs, and detect cancer growth, according to the National Cancer Institute. Experts are trying to treat SARS-CoV-2 with nanomedicine, as nanoparticles with 10-200 nm size can detect, for sitespecific transfer, SARS-CoV-2, exterminate it, and improve the immune system of the body. Nanotechnology could help to combat COVID-19 by stopping viral contamination. Highly accurate nano-based sensors will be made in the future that will quickly recognize the virus and act by spraying to protect frontline doctors and the public. Furthermore, many antiviral disinfectants are being developed through nanobiotechnology to stop virus dissemination. In the future, nanotechnology will evolve to develop drugs with high activity, less toxicity, and sustained release to target tissue. Therefore, personalized medicine and nanomedicine both will be potential therapies to treat COVID-19 successfully, as well as to treat upcoming diseases in future.