1.     Introduction

Chronic kidney disease (CKD) affects more than 10% of the global population, and its prevalence is rising because of part to the increased prevalence of disease risk factors such diabetes, hypertension, obesity, and advanced age [1]. About 1.33 million individuals are impacted by AKI each year, a complex condition with multiple etiologies that has a major impact on hospitalization and death rates, particularly for patients who are critically unwell.

The rapidly expanding subject of nanomedicine uses nanomaterials to identify and treat diseases. Examples of applications are tailored nanodrug therapy for kidney disease and non-invasive nanomaterial-based nerve damage diagnostics. In recent years, there has been a notable advancement and promise for rapid development in the field of pharmaceutical and nanoscience research.

Drugs with targeted and controlled release capabilities can be delivered via a variety of organic, inorganic, and polymer nanomaterial forms, such as liposomes, nanoparticles, polymeric nanoparticles, lysozymes, elastin-like polypeptides, nanogel, lipid-based nanocarriers, and chitosan. Nano-drug delivery overcomes the limitations of conventional treatment by enabling medication targeting and prolonged release, particularly for medications with low solubility, limited absorption, and low accumulation in target organs. From, parameters, surface characteristics, hydrophobicity, and more [2,3]

A.   The kidney's anatomical foundation as a multipurpose target organ for therapy.

Around a million nephrons, glomeruli that perform filtration, and renal tubules that perform reabsorption constitute the kidney. Unique cell types, a complicated structure, and pathological characteristics in each nephron can indicate CKD or AKI. It controls numerous body functions that might require medical attention, such as blood pressure, the excretion of metabolic waste, the body's water and electrolyte balance, and acid-base balance. The most popular types of nanocarrier materials for drug administration are those that target the kidneys either directly, indirectly, or through other means.

B. Drug based on nanomedicine that Actively targets the kidneys

Receptor ligands for renal tubular cells and particular proteins for glomeruli are two examples of functional groups or bioactive chemicals that can be added to the surface of nanomaterials to improve their affinity and targeting ability and enable more efficient interaction with kidney tissues. Peptides and immunoglobulin constitute nearly all of these particular functional groups, or bioactive chemicals; the most commonly used form is an antibody. By binding to antigens on some cell membranes, nanoparticles can specifically enter target cells. However, the particles become much wider and lose some of their ability to filter when antibodies attach to them. In many aspects, peptide chains are superior to anti-bodies because they maintain specificity without significantly increasing the particle's bulk using nanoparticles.[4]

C.   Passive targeting of nanomedicine-based drug to the kidneys

After the blood passes through the filtration barrier inside the capillaries, the filtrate reaches the renal tubule system. Fig1 represent the filtration barrier is made up of endothelial cells, podocytes, and the basement membrane. Drugs based on nanomedicines have the ability to pass through the filtration barrier and enter the target cells through urine production in order to be passively targeted. This places stringent limitations on the nanoparticles' characteristics, including the following: First to emerge is particle size. Particle size has a major impact on drug absorption, as studies have shown that the fenestrations of the glomerular capillaries (diameter 60–80 nm) and the slit diaphragms formed at the podocyte foot processes (diameter 12–22 nm) form a physical barrier for blood filtration in theglomerular filtration barrier.[5]

D.   Drug administration by nanoparticles to the kidneys is made feasible by the complexity of renal cells.

Mesangial cells, which are found in the glomerulus, also aid in controlling the glomerular filtration barrier's surface area and the blood flow throughglomerular capillaries. They also produce signaling factors and offer structural support to the glomerular

Fig1. Materials meant for nanodrugs passively target the kidneys. The filtration barrier and the urinary system are both crossed by medication delivered to target cells via nanoparticles. [5]

capillaries. Mesangial cells represent another potential target for pharmacological treatment, since mesangial cell illness is linked to increased mesangial cell proliferation in a variety of renal illnesses and plays a critical role in various glomerular disorders. Additionally, it is more likely that 80–100 nm-diameter nanoparticles will remain in the circulation and kidneys longer before being filtered[6]. This allows them to be quickly collected by the RES/MPS and makes them perfect for targeting the glomerular structure.

E.Chronic kidney Disease (CKD)

Chronic kidney disease (CKD), which lowers kidney function, has several etiologies. The discussed endpoint phenotype is interstitial fibrosis, which has a similar overall prognosis and necessitates dialysis or transplantation. The reduced renal clearance exacerbates the pharmacokinetic and toxicological limitations of the current therapies. Recent advancements in the regulated, targeted, and simplified administration of small molecules and biologics employing nanoparticles have opened up new possibilities for multidirectional therapies.

F. Kidney Interstitial Fibrosis

Among histologic features, Myofibroblasts are primarily responsible for renal fibrosis. Nitric oxide (NO) is toxic to myofibroblasts, but because NO has a broad spectrum of effects on other tissues and a poor bioavailability, systemic NO treatment for fibrosis is not feasible. The pH-responsive micelle-loaded donor molecules were designed to release their payload in acidic environments (the lysosome within the cell as well as areas where tissue damage is still present). In kidneys with fibrosis, these nanoparticles had improved uptake and significantly reduced fibrosis. Certain nanoparticle compositions have shown promising in the kidney, repurposing antifibrotics that were previously approved for other uses. Targeted peptide-based nanoparticles containing the multi-kinase inhibitor Sorafenib—approved by the FDA to treat a number of carcinomas—were found to reduce renal fibrosis and suppress myofibroblast activation. Metformin has antifibrotic effects on kidneys and other organs when taken at a level five times higher than that of its usual diabetes treatment. Moreover, this fibrosis treatment is unsuccessful since decreasing GFR increases the possibility of metformin-associated lactic acidosis. When metformin was incorporated into nanoparticles and targeted towards RTEC, it demonstrated enhanced anti-apoptotic, anti-inflammatory, and anti-fibrotic properties[7].

Renal inflammationhas a well-established role in AKI; however, the systemic anti-inflammatory drug treatment may be limited in its efficacy by several adverse effects. Co-loading anti-inflammatory medications specific to the kidney into nanocarriers combined with treatments for a different damage mechanism has been tested to improve AKI reduction. For example, because chemokine receptor 4 (CXCR4) is abundantly expressed in injured RTEC and enhances leucocyte recruitment during AKI, injection of CXCR4 a nanoparticles successfully reduced inflammation and AKI. CXCR4a NP surface chemical modifying is a means to improve kidney targeting [8]. Cell free DNA (cfDNA) is abundant during AKI and is likely to aggravate local inflammation. Mn₃O₄ nanoflowers acted as cfDNA scavengers to lessen kidney injury.

2. Overview of targeted drug delivery systems

Drugs that can be applied topically or injected throughout the body to concentrate and localize treatment into particular organs, tissues, cells, or intracellular structures are held in carriers called targeted drug delivery systems, or TDDSs. Pharmaceuticals can only be categorized as TDDSs when they meet five requirements: biocompatibility, controlled release, non-toxicity, placement (releasing the medication at the specified area), and biodegradability[9]. Targeted drug delivery aims to reduce adverse effect occurrence and improve therapeutic effectiveness. Enhancements in dosage techniques further enhance safety, efficacy, dependability, and patient adherence; consequently, TDDSs are becoming more widely accepted by the international medical community[10].

3. Kidney-TDDS

A.     Nanoparticles

Nanoparticle drug delivery is an efficient drug delivery method that has generated a lot of interest in the world of drug delivery due to its many benefits. Nanoparticles increase the concentration of the medication in the target cell or tissue because they are so small that they can pass through cell membranes and blood artery walls. Nanoparticles can be designed as controlled release systems that achieve slow and continuous drug release while maximizing benefits and limiting side effects by adjusting the features and structure of the particles. The body may employ many nanoparticles without concern since their compositions include components that are both biocompatible and biodegradable, which will eventually break them down through biological processes. Drug stability can be improved by encasing medications in nanoparticle carriers, which can shield them from environmental stresses such pH variations and enzyme deterioration[11].

B.     Nanogels

Hydrogel nanoparticles, which are particles that combine the characteristics and uses of hydrogels with nanomaterials, are another name for hydrogels. Hydrogels are produced through an easy process that requires one or more monomers and a significant amount of water to create three-dimensional networks of polymers. These nanoparticles have a diameter ranging from 20 to 10,000 nm and can be produced in several methods. Nanogel materials can absorb water because of the hydrophilic functional groups on their polymer backbone, but they are impermeable to water because to the cross-linking of their network chains. Nanogel nanoparticles possess better drug loading capacity, longer release characteristics, stronger permeability, and a bigger, variable specific surface area than conventional nanogel drug carriers.[12]

C.     Liposomes

Liposomes are small, phospholipid-based, hollow, spherical structures that are used as nanocarrier systems. They are typically between 100 and 200 nm in size. A bilayer membrane made of one or more phospholipid molecules encloses a watery interior compartment. By creating an interface between the two media, liposomes can effectively encapsulate and transport drugs that are soluble in lipids and water due to the hydrophilic and hydrophobic properties of this structure.

D.     Polymeric Nanoparticle TDDSs

Research in medical biology is showing an increasing interest in polymeric materials because of their low toxicity, controlled release, longer cycle duration, biodegradability, and ability to deliver drugs.

a) Polyamidoamine Dendrimers

It has been demonstrated that PAMAMs with negatively or neutrally charged groups attached exhibit reduced toxicity due to strong electrostatic interactions with cell membranes. PAMAMs are useful dendrimers in the realm ofdrug administration because they improve drug solubility, stability, and bioavailability while streamlining manufacturing processes. Renal tubules are the target of a prospective delivery mechanism called serine-modified PAMAMs.

A part of the pathophysiology of renal I/R damage involves nitric oxide (NO). Medications that are physiologically active and release NO into the body are known as NO donors. However, a considerable number of NO donors are needed to prevent renal I/R injury, and the majority of those that are available are dispersed throughout the kidney. Katsumi et al. developed the kidney-targeted NO donors known as S-nitrosyl-L-serine-modified PAMAMs (SNO-Ser-PAMAMs). Multiple S-nitrosothiols (NO donors) are covalently attached to L-serine-modified dendrimers. Intravenous infusion of SNO-Ser-PAMAMs significantly decreased blood creatinine levels and improved kidney histological damage in a rat model of renal ischemia–reperfusion (I/R) injury. According to studies by Matsuura et al. and Katsumi et al., CAP and NO donors can be encapsulated by dendritic macromolecules that have a specific serine binding modification. Second, reticuloendothelial system (RES) often recognizes larger PAMAMs, whereas the kidneys can easily remove smaller PAMAMs. By increasing the toxicity profile and vector clearance rate, surface modifications have been used to lessen these effects[13].

b) Exosome TDDS

All cell types secrete extracellular vesicles called exosomes, which have the capacity to store tiny molecules of protein and nucleic acids. The genetic material that the exosomes carry is used in exosome-based treatment to heal the lesion area. However, by altering the medicine and delivering specific drugs to the lesion site, exosomes can serve as organic drug delivery carrier.

The ability of mesenchymal stromal cells (MSCs) to promote self-renewal and facilitate the healing process. By preventing oxidative stress and cell death, MSC-exosomes—also known as MSC-derived exosomes—are thought to be able to reduce the acute kidney damage (AKI) brought on by cisplatin [14]. According to Cao et al., MSC-exos contain damaged renal tubules that express VCAM-1 and intercellular adhesion molecule 1 (ICAM-1) following renal I/R injury carried on by integrins. Exosomes derived from stem cells are believed to contain primarily MiR-125b-5p/p53, which reduces AKI and encourages kidney regeneration. MSC-exos have a tradition of dependability and reliability. Furthermore, MSCs may cause cancer since MSC-exos are subject to immune system elimination after serving their primary purpose.

c) Chitosan

The main byproduct of chitin is chitosan. Chemical reactions or enzymatic methods are used to transform chitin into chitosan. Due to their lower cost, chemical processes are better suited for large-scale production. Polysaccharides are the building blocks of chitosan carriers, which function similarly to ELPs. By scavenging free oxygen radicals, the mitochondria-targeted peptide Szeto-Schiller-31 (SS31) lessens mitochondrial damage. Liu et al. synthesized SC-TK-SS31 by connecting SS31 with l-serine-modified chitosan (SC) via a Thioketal (TK) linker that is sensitive to reactive oxygen species. Increasing the therapeutic efficacy of SS-31, SC-TK-SS31 can form in tubular epithelial cells by modifying L-serine through a specific interaction with KIM-1. By eliminating an excess of reactive oxygen species from tubular epithelial cells, Wang et al.'s stepwise-targeted chitosan oligosaccharide, triphenyl phosphine low-molecular-weight chitosan–curcumin (TPP-LMWC-CUR, TLC), was utilized to treat acute kidney injury (AKI) caused by sepsis. Through its contact with the receptor megalin, TLC is quickly absorbed by LMWCs and subsequently distributed throughout the kidneys. Because of the strong buffering capacity of LMWCs and the positive delocalization charge of TPPs, intracellular TLCs are able to transport CURs to the mitochondria[15].

E.     Micelles

Micelles are thermodynamically stable colloidalaggregates that form when molecules self-assemble in an aqueous solution at a particular surfactant concentration. When surfactants with adsorption ability reach saturation and begin to disperse in the aqueous solution, micelle formation takes place. The hydrophobic groups present in surfactants and water molecules have a stronger repulsion force than attraction. As a result, van der Waals forces cause the hydrophobic groups to assemble in the micelle's core and the hydrophilic groups to form its outer layer, stabilizing the micelle's dispersion in the aqueous solution. Micelles typically have particle diameters between 10 and 100 nm. The micelle's excretion from the body is minimized by its hydrophilic outer shell and tiny nanocore.

F.      Dendrimers

Large molecules, or dendrimers, have a dendritic structure made up of linearly coupled, low-molecular-weight polymers that repeatedly branch. They are categorized as monodisperse, highly branched polymers with three major chains, usually consisting of a polymer core, a side chain composed of dendritic units, and a main chain. Modern drug delivery methods like dendrimers are extensively employed in the pharmaceutical sector. They are rich in surface-active functional groups with adjustable physicochemical properties and possess interior pores. Dendrimers are typically between 1 and 100 nm in size. The primary obstacle to the therapeutic application of dendrimers is their toxicity, primarily due to surface charges. The more polymer produced, the more hazardous the closely spaced cationic surface of dendrimers becomes. Therefore, complex methods are needed to modify dendrimers[16].

Table1.An overview of drug delivery techniques.