Introduction

Kidney is one of the most vital organs in the human body, it plays important roles in maintaining internal environmental stability, excreting metabolic waste, and regulating various physiological processes.1 Dysfunction of kidney will lead to many diseases, including renal tumor, kidney stone, acute kidney injury (AKI), chronic kidney disease (CKD), diabetic nephropathy et al.2 Kidney disease is a significant global public health issue that has profound impacts on individuals, healthcare systems, and socioeconomic structures. Its high prevalence, disability rates, and mortality make it a pressing health challenge that demands attention and intervention.3

Figure 1 Schematic illustration of renal filtration pathways. Small molecules and ultrasmall nanoparticles (< 6 nm) undergo glomerular filtration through fenestrated endothelium (~70–100 nm) and the glomerular basement membrane (GBM), and are subsequently processed by podocytes and proximal tubular epithelial cells (PTEC). Larger or protein-bound drugs are primarily cleared via endothelial transcytosis, a size-independent pathway, entering peritubular capillaries and undergoing tubular luminal and peritubular capillary uptake. The arrows correspond to the primary directional pathways described above.

Figure 2 Impact of renal pathophysiological changes on drug delivery. In pathological conditions, three typical changes might happen: alterations in the renal microvascular network resulting in decreased renal blood flow, damage to the filtration barrier causing excessive filtration of macromolecules, and changes in renal enzyme activity. In addition, kidney diseases are often associated with changes in the expression and activity of key proteins which might be targets for kidney drug delivery.

Figure 3 Mechanisms and strategies of kidney-targeted drug delivery systems. The working modes of renal-targeted delivery systems are primarily categorized into active targeting and passive targeting. Passive targeting mainly depends on the size, charge and shape of drugs or carriers. Appropriate dimensions, positive charges and special shapes can enhance renal passive targeting efficiency. Active targeting refers to transcytosis of epithelial cells or the design of ligands that specifically target kidney biomarkers. The optimal renal targeting effect can only be achieved through the combination of active and passive targeting strategies.

Figure 4 Representative examples of peptide-based renal targeting across kidney diseases. (A–H) Ex vivo imaging analysis of renal targeting efficacy. (I) Fluorescence-based analysis of renal targeting efficiency of KTPs across different kidney conditions. This figure includes cropped selections from published images obtained copyright permission. The numbers presented in figures are PMID of these studies.

Figure 5 Ex vivo imaging of different targeting ligands in diverse kidney condition. (A) Peptides. (B) Targeted aptamers can not only actively bind to specific cells, but also inherently accumulate in the kidneys due to their small molecular size. (C) Antibodies & antibody fragments. (D) Small molecules. (E) Natural ligands. This figure includes cropped selections from published images obtained copyright permission. The numbers presented in figures are PMID of these studies.

Drug therapy and surgical treatment are the two main treatments for kidney diseases. Drug therapy requires a certain concentration of drugs that eventually reach the kidney to be effective. Unfortunately, kidney is a complex organ with many barriers, which make it hard to deliver to. The vascular endothelial cells within the kidneys form a sieve-like structure. The tight junctions between these cells restrict the passage of large molecules and highly polar substances, while small molecules and lipophilic drugs can pass through more easily.4 As drugs pass through the glomerulus, they come into contact with the glomerular basement membrane. The selective filtration function of the basement membrane allows small molecule drugs to pass through, while large molecules or negatively charged drugs may be restricted by its filtration capacity. After drugs enter the renal tubular lumen, they might be reabsorbed across the tubular epithelial cells into the peritubular capillaries. These cells utilize both active transport and passive diffusion mechanisms.5 Importantly, drug entry into renal tissues is not exclusively dependent on glomerular filtration. In addition to the luminal route, therapeutic agents can also access the kidney through the peritubular capillary network, which arises from post-glomerular efferent arterioles. Via this pathway, drugs and nanocarriers in the systemic circulation may directly interact with the basolateral membrane of tubular epithelial cells or renal interstitial compartments, providing an alternative and often dominant route for larger molecules, nanoparticles, and biologics that are not readily filtered by the glomerulus. Moreover, drugs must first travel from the systemic circulation through the renal artery to reach the kidney’s blood supply system. The distribution of drugs in the blood may be influenced by their binding affinity to plasma proteins, such as albumin. Drugs with a high protein-binding rate need to be released in their free before they can enter kidney tissues.6 The location and physiological anatomy of the kidney pose a certain obstacle to the accumulation of drugs in the kidney.

Thus, the kidney presents a formidable yet valuable target for drug delivery. Successfully navigating its intricate physiological defenses is essential to unlock its full therapeutic potential. Kidney-targeted delivery strategies are designed precisely for this purpose, aiming to guide drugs through these barriers to their site of action, thereby maximizing efficacy and safety.7 We divided Kidney-targeted drug delivery system into carrier platforms and Targeting & Functional Moieties. A diverse array of materials, including organic, inorganic, and polymeric nanostructures such as nanoparticles, scaffolds, extracellular vesicles and so on, are served as versatile carriers.8 To bestow these carriers with specificity and controllability, various targeting and functional components are employed, including molecular recognition elements, stimuli-responsive materials, and stealth or stability modifiers.9 Critically, the design of an optimal kidney-targeting strategy requires the synergistic integration of these components with a third, equally vital consideration, the therapeutic cargo itself. Only through the rational co-design of the carrier, functional moieties, and the cargo, can a truly effective and smart delivery system be realized.

Therefore, this review aims to provide a comprehensive and updated analysis of smart drug delivery strategies for kidney targeting. Specifically, we seek to synthesize the fundamental mechanisms underlying passive and active renal targeting and critically evaluate the landscape of carrier systems, targeting moieties, and stimuli-responsive designs. What’s more, we discuss the synergistic potential of combined strategies and identify persistent challenges and future research directions. By presenting this integrated framework, we intend to guide the rational design of next-generation renal therapeutics and bridge the gap between preclinical innovation and clinical application.

Scope and Methodology of This Review

As a comprehensive narrative review, literature searches in PubMed, Web of Science, and Embase, covering publications from the past decade up to January 2026 were conducted. Key search terms included “kidney targeted drug delivery,” “renal nanoparticle,” “kidney targeting peptide,” “stimuli-responsive renal delivery,” and related variants. Our initial retrieval included studies up to March 2025, from which 117 articles were selected based on their relevance, exemplar status, and contribution to illustrating key concepts or technological advances. In preparing this revised version, we extended the search to January 2026, identifying and incorporating 26 additional pertinent studies. Given the narrative and integrative nature of this review, article selection prioritized conceptual relevance and representativeness rather than adherence to a systematic screening protocol with rigid inclusion/exclusion criteria. The selected literature is analyzed through a conceptual framework that first examines targeting mechanisms, distinguishing between passive and active strategies. Then deconstructs delivery systems into carrier platforms, targeting and functional moieties and stimuli-responsive elements. This structure is designed to offer readers a mechanistic understanding of renal targeting and practical principles for the rational design of kidney-targeted drug delivery system.

Biological Basis of Kidney TargetingAnatomical Characteristics of Kidney

The kidneys receive more than 20% of the cardiac output, ensuring that the majority of systemically administered drugs are exposed to the renal vasculature. This extensive perfusion facilitates drug transport to nephron units, where filtration, secretion, and reabsorption occur. However, renal exposure alone does not guarantee therapeutic efficacy, as the unique anatomical and biological features of the kidney critically determine whether drugs can access specific renal compartments.

The nephron, the fundamental functional unit of the kidney, consists of the glomerulus and a connected tubular system. The glomerular filtration barrier (GFB) is a highly specialized and dynamic biological interface rather than a simple size-exclusion filter. It is composed of three integrated layers:5 fenestrated glomerular endothelial cells, the glomerular basement membrane (GBM), and podocytes with interdigitating foot processes bridged by slit diaphragms. While the endothelial fenestrations (approximately 70–100 nm) facilitate high permeability to water and small solutes, the GBM and slit diaphragm provide charge- and structure-dependent selectivity. Importantly, podocytes do not contain rigid “pores”. Instead, the slit diaphragm represents a complex protein network that functions as a dynamic filtration structure, with an effective size selectivity typically described in functional rather than anatomical terms.10

Beyond molecular size and charge, increasing evidence suggests that structural features such as molecular architecture and particle geometry can influence interactions with the GFB. Branched or non-spherical nanocarriers may exhibit distinct hydrodynamic behavior and filtration characteristics compared with conventional spherical particles, thereby affecting their ability to traverse or be retained at the glomerular interface.11,12 These observations highlight that renal filtration is governed by an integrated interplay of size, charge, and structural organization, rather than a single physical parameter.

As blood flows through the glomerular capillaries, negatively charged macromolecules are partially repelled by the anionic components of the endothelial glycocalyx and GBM, whereas small solutes are freely filtered. Although classical filtration favors small molecules, it is now well recognized that the GFB can be functionally bypassed or altered under specific physiological and pathological conditions. Mechanisms such as endothelial transcytosis, disease-induced barrier disruption, and enzyme-mediated transport enable larger molecules or nanocarriers to access renal tissues without strict size-dependent filtration.13

Following filtration, substances entering the tubular lumen encounter renal tubular epithelial cells, which regulate retention and excretion through passive diffusion and active transport processes. The renal tubule comprises distinct segments, including the proximal tubule, loop of Henle, distal tubule, and collecting duct, each of them exhibits unique transport characteristics. Drug behavior within the tubules is influenced by physicochemical properties such as molecular size, charge, solubility, and pKa, as well as luminal pH and transporter expression.14 The proximal tubule, in particular, displays high re-absorptive capacity for water-soluble compounds, while distal segments contribute to acid–base balance and selective drug handling.

In addition to the luminal route, renal drug entry is not restricted to glomerular filtration. Therapeutic agents circulating in the bloodstream may also access renal tissues via the peritubular capillary network arising from post-glomerular efferent arterioles. Through this pathway, drugs-especially large molecules, protein-bound agents, and nanocarriers can interact with the basolateral membrane of tubular epithelial cells or enter the renal interstitium, thereby bypass the filtration barrier altogether.15 Organic anion and cation transporters expressed on tubular cells further mediate active secretion of drugs and metabolites into the tubular lumen.

Collectively, these anatomical and physiological features highlight that renal targeting is governed by multiple, parallel transport routes rather than a single filtration-dependent mechanism (Figure 1). A comprehensive understanding of these pathways is essential for the rational design of kidney-targeted drug delivery systems.

Molecular Mechanisms of Kidney Targeting

Fortunately, the specific molecular expressions enriched in normal or disease kidney, provide several targets with kidney-targeting potential. Several studies4,16 have systematically listed common targets which can be categorized into three main groups: First, targeting proteins highly expressed in podocytes, including FcRn,17,18 VCAM-1,19–21 and αvβ3;12,22 second, targeting E-selectin and P-selectin on endothelial cells (ECs);23,24 third, targeting megalin and cubilin on proximal tubular epithelial cells (PTECs).25,26 By modifying delivery systems to target these molecules, it is possible to enhance affinity with renal cells and increase drug uptake.

Physiological Changes in Kidney Disease States

In pathological conditions, the normal structure and function of the kidneys are impaired, leading to three typical changes: alterations in the renal microvascular network resulting in decreased renal blood flow, damage to the filtration barrier causing excessive filtration of macromolecules, and changes in renal enzyme activity leading to dysregulation of small molecule transport. These changes present both challenges and opportunities for targeting kidney disease. For example, in acute kidney injury (AKI), renal blood flow (RBF) can decrease by 50–60%, and microvascular permeability increases.27 On one hand, the reduction in blood flow decreases the bioavailability of drugs in the kidneys, and the prolonged residence time increases the potential risk of toxicity. On the other hand, the increased permeability of the glomerular filtration barrier (GFB) allows larger nanoparticles to pass through, promoting their accumulation in the kidneys. Additionally, kidney diseases are often associated with changes in the expression and activity of key proteins. For instance, in diabetic nephropathy (DN), the high expression of the renal tubular transporter NHE3 leads to increased sodium ion retention,28 while in renal failure, the accumulation of metabolic waste products and local inflammation suppress the expression of organic anion transporters (OAT1–4),29 further exacerbating toxin accumulation. However, the high reactive oxygen species (ROS) environment provides an opportunity for the design of ROS-responsive kidney-targeting particles,30 and targeting inflammatory cells allows for more precise delivery of drugs to injured kidney cells.31,32 In renal cell carcinoma (RCC), the high expression of CAIX and CD70 has also emerged as potential targeting sites33–35 (Figure 2).

Mechanisms and Strategies of Kidney-Targeted Drug Delivery SystemsKidney Passive Targeting

As mentioned above, the physicochemical properties of drug carriers, particularly size, shape and surface charge, critically influence their renal distribution routes, including glomerular filtration, endothelial transcytosis, and tubular uptake. Factors such as solubility, affinity, and pH further affect drug secretion and reabsorption along the nephron. Importantly, renal passive targeting should not be viewed as a rigid size-threshold-dependent process, but rather as a dynamic and route-dependent phenomenon shaped by both particle properties and renal physiological status.

Regarding molecular size, for kidney-specific targeting, particles must be sufficiently large to avoid rapid clearance from the body when distributed in the renal tubules (> 2 nm), but small enough to reduce, rather than completely prevent nonspecific uptake by the liver, spleen, or lungs (< 100–1000 nm).36 Generally, nanoparticles with a diameter less than 6 nm and proteins with a hydrodynamic diameter (HD) less than 6 nm can successfully pass through the glomerular filtration barrier4,15,37 and are cleared via renal excretion. Nanoparticles around 10 nm temporarily enter the mesangium, but due to the lack of phagocytosis, they do not remain there, while particles larger than 20 nm are less likely to accumulate in the kidneys.16

Notably, renal targeting behavior of ultrasmall nanoparticles is highly sensitive to disease associated alterations in renal clearance pathways. For example, PEGylated glycyrrhizic acid-based nanoparticles (~4.5 nm) exhibit rapid renal elimination in healthy mice due to their size being below the filtration threshold.38 However, in acute kidney injury (AKI) models, impaired tubular clearance and obstructive damage result in enhanced renal retention of the same nanoparticles, as visualized by in vivo PET imaging. This phenomenon exemplifies a size-gated yet disease triggered passive targeting mechanism, in which particle size determines filterability, while pathological conditions dictate final renal distribution.

Although classical filtration favors small nanoparticles, renal accumulation of larger particles has also been reported under specific experimental or pathological contexts. Williams et al observed that nanoparticles with a diameter of about 400 nm showed 7 times higher targeting efficiency in the kidney compared to the heart, lungs, spleen, and liver.39 Similarly, micron-sized microcapsules (~3 μm) have been shown to localize within the kidney under renal-targeted administration conditions.40 Importantly, such renal localization was achieved under renal artery or kidney-targeted administration rather than systemic intravenous injection, and therefore should not be generalized to conventional passive targeting strategies. Such observations are generally attributed to non-filtration-based mechanisms, including mechanical trapping within glomerular capillaries, altered hemodynamics, or direct access from peritubular capillaries, rather than conventional size-dependent filtration.

For ultrasmall nanoparticles (<5.5 nm), surface charge becomes a dominant determinant of renal fate.16 Negatively charged quantum dots (~3.7 nm) preferentially accumulate in mesangial cells, whereas similarly sized cationic quantum dots (~5.67 nm) are rapidly excreted into urine. For larger nanoparticles, renal accumulation is often mediated by active uptake in renal tubules.15 Due to the negatively charged microvilli densely covering the luminal surface of proximal tubule epithelial cells (PTECs), positively charged nanoparticles exhibit enhanced retention and uptake in proximal tubules compared with neutral or negatively charged counterparts.41–44

Beyond size and charge, particle geometry has recently emerged as an additional modulator of renal passive targeting behavior. Nanostructures with distinct shapes, such as dendrimers45 or DNA origami architectures,15 interact differently with glomerular flow dynamics and filtration barriers. Dendritic macromolecules, owing to their highly branched and monodisperse architecture, offer tunable size and surface functionality but may exhibit charge-related toxicity with increasing generation. Meanwhile, shape-defined DNA nanostructures with rectangular, triangular, or tubular geometries have demonstrated unexpected renal clearance and therapeutic efficacy in AKI models, despite dimensions exceeding classical filtration limits. These findings suggest that particle shape may influence renal transport by modulating hydrodynamic behavior, deformation, and barrier interactions, although the underlying mechanisms remain incompletely understood.

Kidney Active Targeting

However, passive targeting often fails to meet the demands for renal targeting in many cases, as non-specific drug distribution increases the risk of systemic side effects. Since these large nanoparticles also exhibit high non-specific distribution, loading targeting ligands into the delivery system is an optimal strategy to further improve renal targeting. Whether directly conjugated with therapeutic agents46 or integrated into nanoparticle carriers,47–50 these strategies have demonstrated enhanced renal accumulation. In addition to targeting peptides, antibodies and natural ligands can also be utilized for active kidney targeting, the category and function of these modification are thoroughly discussed in Targeting and Functional Moieties below. Moreover, due to the abundant expression of specific markers in the kidney diseases, various modification targeting specific markers have shown excellent renal targeting capabilities. For example, the expression of CD44 on renal cells with inflammation is abnormally upregulated.51 Zhi-Wei Huang et al52 developed hyaluronic acid-coated ε-polylysine–bilirubin conjugated nanoparticles that can target CD44 on damaged renal cells and selectively accumulate in the damaged kidneys.

Beyond classical ligand-receptor-mediated endocytosis in tubular epithelial cells, emerging evidence indicates that renal active targeting can also be achieved by promoting glomerular endothelial transcytosis. Recent studies have demonstrated that short amino acid repeat peptides, single amino acid modifications, or prodrug-like surface displays can facilitate carrier transport across the glomerular endothelium via active transcellular pathways rather than passive size dependent filtration. For example, enzyme-activatable dendrimer-drug conjugates responsive to γ-glutamyl transpeptidase (GGT), a brush-border enzyme enriched in glomeruli, enable site-specific drug activation and efficient glomerular delivery through receptor-mediated transcytosis, thereby overcoming physiological filtration barriers.45 Similarly, serine-modified nanocarriers have been shown to enhance glomerular accumulation while reducing hepatic uptake, highlighting the critical role of minimalistic amino acid motifs in regulating endothelial transport behavior.53

In parallel, exosome and small extracellular vesicle (sEV) based delivery systems have emerged as a unique class of renal-targeting nanotherapeutics that combine both passive and active targeting features. Engineered exosomes derived from mesenchymal stem cells or immune cells exhibit intrinsic renal tropism and can be further functionalized to enhance kidney specificity. These vesicles are capable of traversing renal endothelial barriers, evading rapid clearance, and delivering bioactive cargos to glomerular or tubular cells. Recent studies have demonstrated that surface-engineered EVs achieve superior renal accumulation and therapeutic efficacy in models of acute kidney injury and chronic kidney disease, underscoring their potential as next-generation kidney-targeted delivery platforms.

Notably, despite the improved specificity conferred by active targeting strategies, several intrinsic limitations remain.54 First, ligand or peptide modification may increase immunogenicity and accelerate systemic clearance. Wilson W. K. Cheng et al55 found that antibody-modified liposomes exhibited 4-5-fold higher blood clearance rates compared to non-targeted counterparts. Second, many active targeting pathways rely on endocytosis, which may lead to lysosomal degradation of encapsulated biologics, such as proteins or nucleic acids, thereby compromising therapeutic efficacy.56 These challenges highlight the necessity of integrating transcytosis-based transport, enzyme-responsive activation, and vesicle-mediated delivery to optimize renal targeting outcomes. Importantly, active targeting rarely overrides the fundamental constraints imposed by renal passive targeting, and in most cases only marginally enhances renal accumulation within the physicochemical boundaries established by carrier size, charge, and circulation behavior. Therefore, passive and active targeting should not be viewed as independent strategies, but as interdependent design layers that must be co-optimized.

Interplay Between Passive and Active Targeting Strategies

Rather than functioning as two independent modules, passive and active targeting strategies are mechanistically interdependent in kidney-targeted drug delivery systems. Passive targeting, governed by particle size, shape, surface charge, and circulation behavior, determines the initial renal exposure of drug carriers, whereas active targeting primarily refines cellular or sub-organ localization within the constraints imposed by passive biodistribution.

In this context, drug carriers with inherent renal accumulation properties can provide a favorable biodistribution background, upon which ligand-mediated targeting further enhances specificity. For example, elastin-like polypeptide (ELP), a carrier known for its preferential renal uptake, is frequently combined with kidney-targeting peptides (KTPs). PEG–PLGA vesicles exhibit prolonged circulation and reduced nonspecific uptake due to steric stabilization. However, PEGylation may also reduce cellular internalization efficiency.57 Surface modification compensates for this limitation by enhancing renal cellular uptake, illustrating that active targeting serves to locally amplify the passive renal exposure conferred by PEGylation rather than replacing it.26,47

Notably, as we described above, EVs and exosomes represent an emerging renal delivery paradigm in which passive and active targeting mechanisms are intrinsically integrated. Native and engineered exosomes possess favorable biodistribution characteristics, including nanoscale size and prolonged circulation, while their membrane proteins and engineered surface ligands enable cell-specific uptake and endothelial interactions. Exosome-based delivery systems have demonstrated robust renal accumulation and therapeutic efficacy in multiple kidney disease models, including ischemia–reperfusion injury, chronic kidney disease, renal fibrosis, and anemia.58–63

Collectively, these findings underscore that passive and active targeting strategies are not independent or interchangeable, but rather represent a continuous targeting spectrum shaped by renal physiology and transport mechanisms (Figure 3).

Engineering Building Blocks for Kidney-Targeted Delivery Systems

The rational design of effective kidney-targeted nanomedicines requires a understanding of its core components. This section deconstructs the delivery system into several fundamental pillars, the carrier platforms, the functional moieties that confer targeting, responsiveness, and special properties along with the therapeutic cargo. The ultimate therapeutic efficacy arises from the intelligent integration of these parts.

Carrier Platforms

The materials of carriers decide the fundamental pharmacokinetics, biocompatibility, drug capacity and interaction with biological barriers.

Polymeric Nanoparticles (NPs)

Polymeric Nanoparticles, typically ranging from 10 to 1000 nm, consisting of a solid core surrounded by suitable chemicals that can influence their size and polarity.64 The polymeric materials employed are extensive, primarily encompassing PLGA, cationic natural polymers, synthetic polycations and various functional copolymers or hybrid systems. To provide an overview of this vast landscape, key representative studies are compiled in Table 1.

Table 1 Polymeric Nanoparticles

Poly(Lactic-Co-Glycolic Acid) (PLGA)

Polymeric NPs, particularly those based on biodegradable poly(lactic-co-glycolic acid) (PLGA), are among the most extensively studied carriers due to their excellent biocompatibility, controllable drug release profiles, and ease of surface functionalization. For instance, PLGA NPs loaded with oltipraz demonstrated specific and prolonged retention in ischemic-reperfusion (IR) injured kidneys for up to 10 days,71 while cabozantinib-loaded PLGA NPs (CZ-PLGA-NPs) showed promise as a targeted adjuvant for renal cell carcinoma (RCC) therapy.66 Surface modification with polyethylene glycol (PEG) is a pivotal strategy to enhance hydrophilicity, prolong circulation, and reduce hepatic and splenic clearance.36 This is exemplified by PEG-PLGA nanoparticles (FNPs, 400–500 nm) that showed 26-fold greater kidney-to-heart fluorescence ratio in injured kidneys, primarily relying on passive, pathology-enhanced permeability.67 Similarly, PEGylated PLGA nanoparticles effectively delivered formoterol to renal tubules in the cortex,69 and PEG-PLGA-DiR NPs showed enhanced and sustained accumulation in unilateral ureteral obstruction (UUO) kidneys compared to free dye.68 An optimal particle size for renal accumulation within the PLGA-PEG system was suggested to be around 90 nm.72 Hybrid approaches, such as PLGA nanoparticles coated with chitosan and then modified with a kidney-targeting peptide (KTP) and hyaluronic acid, have also demonstrated strong kidney-specific targeting and accumulation within 24 hours.73 Furthermore, modifications with various targeting peptides, including KTPs, can substantially enhance renal targeting efficiency,47,65 and these specific modification strategies will be discussed in detail in the following section. Additionally, innovative combination strategies, such as complexing PLGA-RSG nanoparticles with SonoVue microbubbles (MBs) to form PLNPs-RSG-MBs, have been developed. Upon ultrasound exposure, this combination strategy was shown to significantly improve renal drug deposition compared to nanoparticles alone, highlighting the potential of physical targeting modalities.70

Cationic Polymers

Cationic polymers exploit electrostatic interactions with the negatively charged glomerular structures to enhance renal retention. Chitosan, a natural polysaccharide derived from chitin, is a prominent example widely used in renal targeting due to its biodegradability, biocompatibility, and inherent positive charge. This cationic nature facilitates its accumulation in the kidneys, there are prominent examples.75,77,78 However, it is important to note that the strong cationic charge of chitosan and similar polymers can also lead to dose-dependent cytotoxicity and nonspecific interactions with plasma components, a challenge that underscores the need for careful design and charge modulation.77 To mitigate these issues and improve performance, various modifications have been developed. Modifications such as PEGylation (PCS) improved oral delivery and renal targeting of salvianolic acid B while potentially moderating surface charge.79 Cationic chitosan-based nanoparticles (COS-SA) also demonstrated good renal targeting, which was maintained even after adsorption of a human serum albumin (HSA) corona.74 Functionalized chitosan, like α-cyclam-p-toluic acid-conjugated chitosan (C-CS), can target the CXCR4 receptor overexpressed in injured kidneys.76 Other cationic systems include poly-L-lysine (PLL) modified with L-serine, which achieved remarkable kidney-specific accumulation for potential radionuclide therapy,53,62 and polyethylenimine (PEI) derivatives.84 Cationic polymeric nanoparticles designed with polypropylene sulfide-polyethylenimine (PPS-PEI) cores and PEG shells combine reactive oxygen species (ROS)-responsiveness with a tuned positive charge for enhanced glomerular targeting.81

Micelles

Micelles, formed from amphiphiles like Pluronics, do well in solubilizing hydrophobic drugs. Their small size favors renal distribution. Kidney-targeting efficiency is evidenced in studies using chitosan-based,87,92 polysaccharide-based,90,93 or peptide-amphiphile micelles50,88,89 while surface modification with ligands like folate25,91 or specific peptides12 can significantly improve the targeting. Beyond intravenous administration, micellar systems have been successfully engineered for alternative routes. Oral formulations, such as kidney-targeted micelles protected within chitosan particles, can survive the gastrointestinal tract and subsequently accumulate in the kidneys, demonstrating the feasibility of non-invasive systemic delivery.89 Similarly, transdermal micelle-loaded patches offer a potential route for sustained renal drug delivery.18,94

Innovative Polymeric Constructs

These include polymeric plerixafor-based polycations (PPs) that target CXCR4,83 polyvinylpyrrolidone-curcumin nanoparticles (PCurNPs) whose renal accumulation is influenced by polymer molecular weight,82 polycaprolactone-polyethyleneimine (PCL-PEI) NPs coated with poly-γ-glutamic acid (PGA) for GGT-mediated renal targeting in diabetic nephropathy,63,85 polymeric nanoplexes (NPX) formed by electrostatic interaction for peptide delivery,80 Poly(ethylene glycol)-polytyrosine nanocomplexes which have demonstrated passive yet significant kidney targeting and prolonged retention.96 Hollow polydopamine nanoshells loaded with drugs, PEGylated, and conjugated with renal tubule-targeting peptides represent another innovative platform showing enhanced renal accumulation.95

Lipid-Based Nanocarriers

Lipid-based nanocarriers, prized for their biocompatibility and various drug-loading, are important for kidney-targeting drug delivery. This class mainly includes liposomes, micelles and solid-core lipid nanoparticles (LNPs), each offering unique advantages for navigating renal physiology. Key studies are summarized in Table 2.

Table 2 Lipid-Based Nanocarriers

Liposome

Liposomes encapsulate drugs in their aqueous core or lipid bilayers. Studies demonstrate their kidney accumulation potential, often enhanced by PEGylation to prolong circulation.98,99 Functionalization can further direct them, such as peptide-conjugated31,103 or sugar/HA-coated variants.101 Recent advancements include the development of ultrasound-responsive liposomes modified with L-serine (LIPs-S@TAK/PFP), which show strong kidney-specific accumulation and prolonged retention.97 Hybrid systems like liposome-nanoparticle hybrids (LNHy), combining a lipid shell with PLGA or gold cores, also show effective renal targeting.105

Lipid Nanoparticles (LNPs)

Lipid Nanoparticles (LNPs) represent a distinct type, primarily recognized for nucleic acid delivery. Unlike the aqueous-core, bilayer structure of liposomes, LNPs feature a solid, non-aqueous core composed of a lipid mixture. This structure is highly effective for encapsulating hydrophobic small molecules, as indicated by Phospholipid lipid nanoparticles (PLNs) achieving sustained renal accumulation of drugs.31 A key conceptual innovation is the Selective Organ Targeting (SORT) platform. By systematically varying lipid composition, for instance, incorporating specific “SORT” lipids like phosphatidic acid (PA), these LNPs can be intrinsically “programmed” to achieve preferential distribution to different organs, including the kidneys, thereby enabling organ-specific delivery through lipid design itself rather than mandatory surface conjugation.100

Other Specialized Lipid Systems

High-density lipoprotein (HDL) nanodiscs are synthetic, discoidal particles (10–15 nm) composed of phospholipids and apolipoprotein A-I mimetic peptides. Their ultrasmall, flat morphology is important for renal filtration. When further functionalized with kidney-targeting peptides (KTPs), these nanodiscs (KT-sHDL) demonstrated nearly 3-fold higher renal accumulation.49 Spanlastic nanovesicles, formed using non-ionic surfactants and edge activators. Their elastic nature is particularly suited for non-invasive administration routes. For instance, transdermal spanlastic coated with cationic guar gum and hyaluronic acid have shown promise for renal-targeted therapy, offering a potential alternative to systemic injections.86 Nanobubbles (NBs) conjugated with targeting ligands can also serve as carriers to enhance the homing and retention of therapeutic cells like mesenchymal stem cells (MSCs) to the kidneys, especially when combined with ultrasound.104

Inorganic and Hybrid Nanoparticles

Inorganic and hybrid nanoparticles have unique physicochemical properties, such as optical characteristics for imaging, catalytic activity, and robust structures for controlled drug release, making them very useful for kidney-targeted delivery. Some Key systems are summarized in Table 3.

Table 3 Inorganic and Hybrid Nanoparticles

Gold Nanoparticles (AuNPs)

Gold nanoparticles (AuNPs), especially when modified with biocompatible ligands like glutathione (GSH), show favorable kidney-targeting. Studies have shown that GSH-modified AuNPs rapidly accumulate in the kidneys within 1–2 hours post administration and can be efficiently excreted via urine, with a distribution profile favoring the kidneys not the liver.61,111 Rapid renal uptake and great ability of self-assembling into drug-loaded platforms make AuNPs effective therapy for conditions like acute kidney injury (AKI).110 Further modifications, such as coating with PEG and phenolic compounds constructed PEGylated and phenol-enriched Au nanorods (Au-M NRs) that show enhanced and prolonged accumulation in the renal cortex of injured kidneys.109

Ultrasmall Carbon-Based Nanomaterials

PEGylated reactive carbon dots (P-RCDs) with diameters around 5–8 nm are innovative “theranostic” platform. Their sub 10 nm size make it easy for passaging through the glomerular filtration barrier, leading to significant and prolonged renal accumulation.112 Selenium-doped carbon dots (Zt-SeCDs) further expand this category, showing rapid renal accumulation and clearance, with significantly higher signals in injured kidneys.106 Hyaluronic acid-conjugated reduced graphene oxide nanoparticles (HA/rGO) represent another carbon-based platform that can be loaded with hydrophobic drugs and shows specific accumulation in injured kidneys over time.108

Silica-Based Nanocarriers

Silica-based nanocarriers include mesoporous silica (mSiO2) and silica-cross-linked micelles (SCLMs), they provide high stability and versatile surface chemistry for functionalization. Kidney targeting can be significantly enhanced by surface modification with LTH peptide, resulting in increased kidney accumulation and reduced off-target distribution in the liver and spleen.26 Furthermore, SCLMs of specific sizes have demonstrated a remarkable ability to selectively accumulate in damaged renal tubules with extended residence times of up to 10 days, highlighting their potential for sustained, pathology-specific drug delivery.113

Hybrid Systems

MOFs (Metal–Organic Framework) offers ultrahigh drug loading, tunable pore size, and easy surface functionalization for targeted delivery, for instance, zeolite imidazolate framework-8 (ZIF-8) nanoparticles coated with renal tubular epithelial cell membranes forming KMZ@FGF21 showed enhanced and prolonged kidney retention of FGF21 compared to unencapsulated controls, with reduced distribution to non-renal organs.48 Gallium nanodroplets (Ga NDs), synthesized from liquid gallium, have shown preferential renal accumulation and rapid urinary excretion, with enhanced retention specifically in injured kidneys.107

Bio-Derived &biomimetic Carriers

Harnessing materials derived from natural biological systems inspire a powerful strategy for kidney-targeted delivery. These carriers can be engineered to mimic natural pathways or exploit specific biorecognition, thereby enhancing kidney specificity and reducing immunogenicity. This section categorizes them into protein and peptide-based systems, cell-mimetic and membrane-derived platforms, and other natural biomolecular carriers, with key examples summarized in Table 4.

Table 4 Bio-Derived & Biomimetic Carriers

Elastin-Like Polypeptides (ELPs)

Elastin-like Polypeptides (ELPs) are thermally responsive, biodegradable biopolymers composed of repeating pentapeptide sequences Val-Pro-Gly-X-Gly. Their modular design allows for precise fusion with therapeutic proteins and functional peptides. Conjugation of a kidney-targeting peptide (KTP) to the ELP has proven highly effective, redirecting biodistribution from the liver to the kidneys and achieving renal accumulation levels 5- to over 150-fold higher than untargeted ELP. This strategy significantly prolongs the half-life of therapeutic cargo in renal tissues and has demonstrated efficacy in models of chronic kidney disease.119–121Recent work has optimized ELP constructs by varying the number of repeating units and amino acid composition to fine-tune renal accumulation, with some constructs showing highly selective and dose-dependent uptake in the renal cortex and proximal tubules.118

Serum Albumin and Derivatives

Cationic bovine serum albumin (cBSA) has a natural affinity of albumin for receptors highly expressed on renal tubular epithelial cells such as megalin and cubilin. CBSA can form stable nanocomplexes with nucleic acids via electrostatic interactions, facilitating targeted delivery to fibrotic kidneys and significantly enhancing renal accumulation compared to free therapeutics.125 Low Molecular Weight Proteins (LMWPs) with their small size (< 30 kDa) and natural renal filtration are served as effective carriers to concentrate conjugated drugs within the kidney.124

Extracellular Vesicle (EVs/Exosomes)

Extracellular Vesicles are endogenous nanovesicles that facilitate intercellular communication. Their membrane is endowed with a rich repertoire of adhesion proteins and receptors, conferring innate tropism for specific cell types. Engineered EVs loaded with therapeutic agents show precise localization to renal tubular epithelial cells, endothelial cells, and macrophages in injured kidneys. Physical methods like ultrasound-targeted microbubble destruction (UTMD) can further enhance their renal delivery efficiency.21 Recent innovations include the use of exosomes derived from mesenchymal stem cells (MSC-Exo) formulated into dissolving microneedle patches for direct, on-site renal application during surgery.115 Furthermore, extracellular vesicles isolated from commercial milk have been successfully loaded with siRNA via electroporation and, upon oral administration, show specific accumulation in injured proximal tubule cells, demonstrating the potential of oral EV-based delivery.117

Cell Membrane-Coated Nanoparticles

Cell Membrane-Coated Nanoparticles involve cloaking synthetic nanoparticle cores with natural cell membranes, creating biomimetic “camouflage.” Platelet membrane vesicles (PMVs), which express P-selectin glycoprotein ligand-1 (PSGL-1), can be coated onto PLGA nanoparticles. The resulting PMV@PLGA complex demonstrates significant and prolonged accumulation in damaged kidney areas over 72 hours by leveraging PSGL-1-mediated targeting to activated endothelium at injury sites.32 Similarly, nanoparticles coated with neutrophil-derived membranes utilize the same PSGL-1 mechanism for targeted delivery to injured renal endothelial cells.122 A sophisticated biomimetic system combines upconversion nanoparticles (UCNPs) encapsulated in thylakoid membranes and further cloaked with activated renal tubular epithelial cell membranes (RECM). This dual-membrane “UCTR” platform achieves highly disease-selective targeting to injured renal tubules, with minimal uptake in healthy kidneys.114

Melanin Nanoparticles (MNPs)

Melanin Nanoparticles (MNPs) are derived from the natural pigment melanin, known for its biocompatibility, biodegradability, and strong antioxidant properties. They also serve as excellent photoacoustic (PA) imaging agents. When functionalized with targeting ligands, they can achieve targeted accumulation in the kidney, allowing for simultaneous therapy and imaging, although significant distribution to the reticuloendothelial system like liver and spleen may still occur.123

Natural Polysaccharides and Conjugates

Inulin (IN) is a natural, water-soluble polysaccharide generally recognized as safe material. Due to its small hydrodynamic diameter, it is readily filtered by the kidneys. Conjugation of drug molecules to inulin such as IN-FeA or IN-EDA-FeA creates kidney specific prodrugs that significantly enhance drug delivery to the kidneys while markedly reducing off-target distribution in other major organs.126 Fucoidan, a sulfated polysaccharide, has been exploited for its P-selectin targeting ability. Self-assembled nanoparticles based on fucoidan conjugated with 4-PBA show dual-targeting, upon oral administration, achieve predominant accumulation in the kidneys, improving oral bioavailability and enabling kidney targeted therapy.127

DNA Tetrahedral

DNA-based nanomaterials offer precise structural control for renal targeting. Ren et al designed a 4.8 nm DNA tetrahedral nanocage loaded with a hemin-G-quadruplex complex.116 In healthy mice, it was rapidly cleared via glomerular filtration within 2 h. However, in acute kidney injury (AKI) models, the same nanocage showed prolonged retention (≥4 h) specifically in renal tubules, demonstrating disease-selective accumulation. This work highlights how ultrasmall, structurally defined DNA carriers can exploit pathological changes in kidney permeability to achieve targeted delivery, providing a novel carrier platform.

Targeting and Functional Moieties

A targeted delivery system relies not only on the carrier itself but also heavily on various modifications applied to the carrier. Some of these modifications can enhance the overall stability of the system and significantly improve its renal targeting efficiency. Furthermore, for systems designed to enable condition-responsive drug release, the design and composition of such modifications are critically important (Table 5).

Table 5 Molecular Recognition (Ligands)

Molecular Recognition (Ligands)Peptides & Aptamers

Peptide-based ligands are one of the most widely studied targeting moieties, owing to their design flexibility, moderate immunogenicity, and ability to mimic natural protein-protein interactions. The kidney-targeting peptide (KTP), which binds to megalin and cubilin on proximal tubular epithelial cells, is a prominent example and has been successfully integrated into various delivery platforms, demonstrating enhanced renal accumulation across multiple studies.47,48,50,73,85,89,95,119–121,123 Beyond its foundational role, the versatility of peptide-based targeting is further illustrated by its successful application across a spectrum of kidney diseases. Figure 4 synthesizes ex vivo imaging and quantitative data from multiple studies, indicating the significant renal accumulation achieved by peptide-functionalized carriers in diverse pathological contexts. While KTP serves as a prominent exemplar in this category, it is important to note that a growing repertoire of disease-specific peptides has been developed to address distinct renal pathophysiologies. This collective evidence underscores peptides as a highly adaptable and effective class of targeting ligands, capable of being tailored to various renal cell types and disease states. These include the RIPΔ peptide targeting TGF-βI,128 the ZPDGFβR affibody for platelet-derived growth factor β receptor,128 a CD70-targeting peptide for renal cell carcinoma,33 the fibronectin-binding pentapeptide CREKA,103 the VCAM-1-binding peptide VHPKQHRGGSKGC,31 the LRG1-specific ET peptide,131 the megalin-binding LTH peptide,26 the RGD peptide for integrin αvβ3,89 and the RWrNM peptide also targeting αvβ3 integrin.12 While peptides offer modular design and good biocompatibility, their susceptibility to proteolytic degradation and modest binding affinity in some cases has spurred the development of alternative ligand classes. Among these, aptamers represent a promising nucleic acid-based targeting strategy, characterized by high specificity, tunable affinity, and enhanced stability against enzymatic degradation. One notable example is RLS-2, which targets EPB41L5 of injured podocytes in Glomerular Diseases, it’s remarkable that Both RLS-2 and the scrambled control aptamer exhibited primary accumulation in the kidneys, this biodistribution profile aligns with the known pharmacokinetics of small nucleic acids and confirms the efficient renal delivery of the aptamer platform, which is a prerequisite for targeted podocyte therapy.132

Antibodies & Antibody Fragments

For applications requiring high affinity and established clinical relevance, antibodies serve as powerful targeting tools. They provide precise recognition of overexpressed renal antigens, such as in the case of an anti-GPR97 antibody for injured tubular cells,123 the cG250-TNF antibody targeting CAIX in renal cell carcinoma,102 PSGL-1 for P-selectin on inflamed endothelium,122 and an anti-α8 integrin antibody for fibrotic kidneys.138

Natural Ligands & Small Molecules

Beyond antibodies, natural ligands offer a distinct advantage by leveraging intrinsic biological recognition pathways, which often result in lower immunogenicity and enhanced biocompatibility. In addition to synthetic ligands, natural ligands are frequently employed to exploit inherent biorecognition pathways within the kidney. This category includes L-serine, which targets the ASCT2 transporter;53,97 2-glucosamine, BSA, and HSA, all targeting megalin;87,135,136 fucoidan for P-selectin;93 glucose for glucose transporter 1 (GLUT1) in diabetic nephropathy;137 hyaluronic acid (HA) for CD44 on injured cells;101,133 folic acid for FRα;91,130 and various integrin ligands (α4β1, α5β1, αLβ2, αMβ2) that bind to VCAM-1/ICAM-1.21

Complementing these biological and macromolecular approaches, small molecule ligands provide unique benefits such as ease of synthesis, structural versatility, and the potential for oral bioavailability. Finally, small molecule ligands represent another important class, particularly for targeting specific receptors implicated in kidney pathology. Examples include polymeric plerixafor83 and α-cyclam-p-toluic acid,76 both of which target the CXCR4 receptor, as well as acetazolamide derivatives designed for CAIX in renal cell carcinoma.34

The comparative efficacy of these diverse ligand classes-spanni