Pathways to translation for nanomedicine in nephrology

ABSTRACT

Kidney diseases are a substantial worldwide health burden, with high mortality and increasing incidence. Despite their prevalence, substantial gaps remain in the clinic in both diagnostics and therapeutics. Many novel treatments have failed in clinical trials or fallen out of use in the clinic due to side effects and poor efficacy, in large part due to poor therapeutic profiles in the kidney. Nanomedicines have begun to emerge as a potentially promising diagnostic or therapeutic delivery system. Based on their physicochemical properties, such as size, shape, surface chemistry, and so on, some nanotechnologies can target the kidneys. However, as of yet, no kidney-specific nanomedicines have reached clinical translation. While the field of renal nanomedicine is in its early stages and growing, some potential obstacles to translation include poor preclinical models, challenges in manufacturing scale-up, clinical trial design and the cost of translation. Here, we overview the current state of the kidney-targeting nanomedicine field and outline a potential framework for clinical translation. We focus on the paths of US Food and Drug Administration– approved nanomedicines and suggestions from other nanomedicine fields to inform our key considerations for translational success. We also highlight the importance of academic and clinical collaboration with industry and federal regulators. Several investigational technologies are just now at the cusp of scaling towards the clinic and we therefore aim to support this momentum for improving the lives of patients with kidney diseases.

INTRODUCTION

Kidney diseases

Both acute kidney injury (AKI) and chronic kidney disease (CKD) pose significant healthcare challenges with various aetiologies, including diabetes, heart failure, genetic conditions and nephrotoxic medications [1–3]. AKI is characterized by an abrupt loss of kidney function, leading to the inability to filter waste products from the blood, typically occurring within a matter of hours [4]. In contrast, CKD represents a progressive decline in kidney function, often associated with the accumulation of fibrotic tissue in the tubules and/or the glomeruli. Globally, AKI affects >13 million individuals, whereas CKD impacts ≈800 million people [5, 6]. Both chronic and acute kidney diseases can progress to end-stage kidney disease (ESKD) depending on their severity and the presence of comorbidities. ESKD is defined as irreversible kidney failure and reportedly affects ≈800 000 patients in the USA [7]. Despite the high prevalence of kidney diseases, diagnostic methods and treatment options remain limited.

Current diagnostic tests, such as serum creatinine levels and glomerular filtration rates (GFRs), tend to have a low sensitivity and typically detect changes during later stages of disease progression [8]. Although novel biomarkers like kidney injury molecule-1 (KIM-1), cystatin C and N-acetyl-β-d-glucosaminidase (NAG) have shown promise [9–11], none have yet become the standard in clinical practice. By combining multiple biomarkers, it may be possible to develop more reliable, non-invasive diagnostic methods [12]. Furthermore, nanosensors hold potential for accelerating detection, enabling continuous monitoring and providing multiplexed biomarker sensing, which could significantly enhance early diagnosis and monitoring of kidney diseases.

Currently there are no optimal treatments available for kidney disease [13]. Most existing therapies focus on slowing the disease's progression rather than reversing the injury or addressing underlying renal tissue damage. For ESKD, treatments typically involve chronic dialysis or kidney transplant [13]. Treatments for AKI and CKD aim to slow progression by monitoring blood haemodynamics, managing underlying conditions such as infections or hypertension and discontinuing nephrotoxic medications. Renin–angiotensin–aldosterone system (RAAS) inhibitors are commonly used to slow the progression of kidney disease. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are examples of RAAS blockers that help slow renal disease progression, while sodium–glucose cotransporter 2 (SGLT2) inhibitors have also shown efficacy [14–16]. Investigation into new kidney disease therapeutics has historically been hampered by issues with target localization and binding [17], resulting in unsuccessful clinical trials. Successful drug targeting remains a complex challenge due to unique aspects of kidney function and anatomy, such as the glomerular filtration barrier, multiple renal compartments and complex renal microcirculation, which can hinder drug uptake [18].

Nanomedicines in the clinic

Nanomedicine refers to the application of engineered nanoscale materials, ranging from 1 to 1000 nm, to improve human health [19]. By encapsulating small molecule drugs or other therapeutic agents in nanocarriers, these medicines can efficiently cross biologic barriers and preferentially accumulate in target tissues, reducing off-target effects. Additionally, nanocarriers enhance pharmacologic properties, such as controlled release and protection against degradation. Many therapeutic nanomedicines have been designed to treat various conditions, with a major focus on cancer treatments [20]. Since the 1995 US Food and Drug Administration (FDA) approval of Doxil (liposomal doxorubicin), ≈100 nano-based formulations have gained approval [21]. That original approval of Doxil launched substantial additional nanomedicines and clinical development (Fig. 1). Well-known examples include lipid nanoparticles used for encapsulating messenger RNA (mRNA) in the Pfizer and Moderna coronavirus disease 2019 (COVID-19) vaccines.

Figure 1:

Historical timeline of several examples of therapeutic nanomedicine approvals by the FDA [24–31].

Examples of nanomedicines can also be seen in the clinic with imaging agents and diagnostic tests. For example, iron oxide nanoparticles (e.g. Lumiren and Combidex) are used as contrast agents in magnetic resonance imaging (MRI), improving scan sensitivity and resolution [22]. Gold nanoparticles are commonly used in diagnostics such as lateral flow assays due to their unique optical properties [23]. This technology is used in rapid COVID-19 antigen tests and at-home pregnancy tests, where the presence of the target antigen binding of the antibody-bound gold nanoparticle is visualized as a pink line on the test strip [23].

Despite these advances, therapeutic nanomedicines face a significant translation gap, mirroring that in other fields of pharmaceutical development, with about a 6% success rate from phase I trials to clinical approval [32]. Challenges include insufficient targeting and physiological differences between preclinical models and humans [33, 34]. Here we propose a framework for translating kidney-targeting nanomedicines, inspired by successful nanomedicines and cross-disciplinary recommendations.

PRECLINICAL KIDNEY-TARGETING NANOMEDICINES

Nanomedicines provide a promising approach for the targeted delivery of therapeutic and imaging agents to the kidneys. There has been a substantial increase in the number of publications in the field of kidney-targeting nanoparticle systems over the past decade. More than 20 review articles have been published [35–47, 18, 48–54], with a surge in interest in kidney-targeting nanomedicines in 2024 [17, 55–66]. Reviews have focused on various aspects of the kidney drug delivery systems, such as the physicochemical properties of nanoparticles needed for kidney targeting [39, 42, 44–46, 18, 56], targeting to particular cell types and tissues in the kidneys [40, 41, 44, 47, 49, 53] and treatment of various kidney diseases [42–44, 48–52, 54, 55, 60, 65]. However, none to date have focused on the path forward, moving from a flourish of preclinical studies to patient impact.

Recent years have seen an increase in research on kidney-targeting nanomedicines. These systems aim to deliver therapeutics and imaging agents directly to the kidneys, addressing various kidney diseases. In our 2024 analysis, 61 publications focused on nanoparticle applications for the treatment of kidney diseases [17]. In the 1 year since its publication, we found 26 additional publications on this same topic [67–92]. A variety of materials are being used in kidney-targeting nanoparticles, with the most common class being polymeric nanoparticles (53 publications, >60% of the nanocarriers found in our analysis). The other material classes being investigated for kidney targeting are inorganic nanoparticles (12 publications) and protein, peptide and nucleic acid nanoparticles (9 publications). Outside of those recent studies, over the past decade several of those nanoparticle systems have gone beyond a single publication, demonstrating several follow-up studies focused on translational development (Table 1; threshold for inclusion was a minimum of three papers using the system).

Table 1:

Renal nanomedicines that have been published more than three times.

Nanomedicine	Renal tissue selectivity	Published applications	Stage of development
Polymeric nanoparticles
Mesoscale nanoparticles [93, 94, 108–114]	26-fold kidney targeting, specific to tubular epithelial cells [94]	Treatment of ischaemic AKI [108, 114, 118, 120], unilateral ureteral obstruction [111], cisplatin-induced AKI [109, 110] and CKD [119], hypertensive CKD [116], diabetic kidney disease [115]	Preclinical rodent models
Chitosan/siRNA nanoparticles [97, 132–134]	7–8% of the injected siRNA accumulated in the kidneys [132], specific to proximal tubule [133]	Proximal tubule–specific gene knockdown [133], treatment of unilateral ureteral obstruction-induced kidney injury [134]	Preclinical rodent models
Poly (amidoamine) dendrimers [95, 135, 136]	Up to 81.7% injected dose accumulated in the kidneys, specific to proximal tubule [95]	Prevention of renal ischaemia–reperfusion injury [135, 136]	Preclinical rodent models
Polycation siRNA nanoparticles [107, 137–139]	Accumulation in the glomerular mesangium (selectivity not indicated) [107]	siRNA delivery to glomerular mesangium [107]	Safety evaluated in non-human primates [139]
Glycol chitosan micelles [98, 140, 141]	Up to ≈0.02% ID/g of kidney tissue accumulated in podocytes and proximal tubular epithelial cells [98]	Treatment of lupus nephritis [140] and Alport syndrome [141]	Preclinical rodent models
Polycaprolactone-polyethyleneimine nanoparticles [142–144]	Accumulation in the kidneys 2–4 times higher compared with liver, lung and intestine (localization within the kidney not specified)	Treatment of diabetic nephropathy [142–144]	Preclinical rodent models
BAPTA-AM nanoparticle [101, 145, 146]	Unquantified kidney accumulation with localization to tubular epithelial cells and endothelial cells [99]	Treatment of ischaemia–reperfusion AKI [101, 145, 146]	Preclinical rodent models
CXCR4-targeting nanoparticles [104, 147, 148]	Accumulation in ischaemia–reperfusion AKI kidneys with 1.8 kidney:liver ratio and up to 2.5-fold increased uptake in injured kidneys compared to sham control, specific to tubular cells [147]	Treatment of ischaemia–reperfusion [104, 147] and cisplatin-induced [148] AKI	Preclinical rodent models
Layer-by-layer assembled polymeric gene-carrier nanoparticles [83, 102, 149]	Accumulation in tubule epithelial cells, mesangial cells, and interstitial fibroblasts [102]	Treatment of UUO [83, 102] and folic acid–induced [83] CKD, contrast-induced AKI [149]	Preclinical rodent models
Melanin nanoparticles [84, 103, 150, 151]	Targeting to tubular epithelial cells, however, kidney accumulation is several-fold lower compared with liver [103]	Treatment of rhabdomyolysis-induced AKI [84, 150], ischaemia–reperfusion AKI [103], diabetic nephropathy [151]	Preclinical rodent models
Lipid nanoparticles
Peptide amphiphile micelles [71, 99, 121–127]	1.25:1 kidney to liver accumulation in mice [122] and 1.14:1 in a pig [127], specific to tubular epithelial cells [99]	Treatment of ADPKD [71, 124, 125, 127]	Kidney targeting evaluated in porcine model
Protein and nucleic acid nanoparticles
Albumin nanoparticles [100, 105, 152–154]	Accumulation in mesangial cells (selectivity not indicated) [105], or tubular cells [100, 153, 154] with ≈2-fold lower accumulation in the kidneys compared with liver [100]	Treatment of mesangioproliferative glomerulonephritis [105], UUO-induced renal fibrosis [152], ischaemia–reperfusion AKI [100, 153]	Preclinical rodent models
Tetrahedral frame nucleic acid nanostructures [96, 155, 156]	Accumulation in the kidneys comparable or slightly higher than in the liver, specific to tubular epithelial cells [156]	Treatment of ischaemia–reperfusion AKI [96, 155] and cisplatin-induced AKI [156]	Preclinical rodent models
Inorganic nanoparticles
Carbon nanotubes [128–131]	About 22% of injected dose accumulated in the kidneys, specifically in proximal tubular cells [129]	Treatment of cisplatin-induced AKI [129]	Pharmacokinetics studied in non-human primates

A key attribute of kidney-targeting nanocarriers is their tissue and/or cell tropism, allowing therapeutic delivery to specific disease sites. The majority of kidney-targeting nanoparticle platforms found in the literature (Table 1) localize to the tubular epithelium through various targeting strategies (Fig. 2). Several systems use passive size-based targeting, particularly mesoscale nanoparticles with a size of 300–500 nm that transcytose into tubular epithelial cells from peritubular capillaries [93, 94]. Other examples are renal-clearable nanoparticles that have a diameter of <10 nm and are filtered through the glomerular basement membrane with some partial reabsorption through various mechanisms into the tubular epithelium [95, 96]. Other nanocarrier systems targeting the tubule act through active mechanisms, such as targeting to the receptors selectively expressed in healthy tubular epithelial cells (megalin [97–100]) or overexpressed in the presence of tubular injury (CD44 [101–103], CXCR4 [104]).

Figure 2:

Nanoparticle strategies for targeting different parts of the nephron.

Several nanoparticle systems also target different cell types within the glomerulus (Fig. 2). Mesangial cells have been targeted using nanoparticles able to pass through endothelial fenestrations [105], which have a diameter of 80–150 nm [106]. Albumin nanoparticles with a size of ≈95 nm were shown to maximize uptake in the mesangial cells [105]. There are also several active targeting strategies that promote nanoparticle accumulation in mesangial cells using targeting ligands such as transferrin, mannose [107] and hyaluronic acid [102]. Another cell type that can be targeted by nanoparticle drug delivery systems are the podocytes, which also express megalin receptors that bind to ligands on nanoparticles, like chitosan [98].

The kidney-targeting nanoparticle system that has the largest number of published studies to date (n = 17) are polymeric mesoscale nanoparticles (MNPs). Due to their size in the mesoscale range (300–500 nm) and PEGylated surface, they demonstrate highly selective kidney accumulation, with little to no accumulation in any other organs [94]. These particles localize primarily to tubular epithelial cells through peritubular transcytosis, as the particles are well beyond the glomerular filtration size limit. MNPs were originally formulated using poly(lactic-co-glycolic) acid (PLGA) conjugated to acid-terminated polyethylene glycol (PEG), which are both FDA-approved biocompatible and biodegradable polymers [93]. They degrade over the course of weeks, which ensures a prolonged therapeutic effect, and demonstrate no systemic or local toxicity in mice [94, 108]. MNPs have been used to deliver a variety of therapeutic payloads, including numerous hydrophobic small molecules [90, 108–114] and hydrophilic biologic molecules [small interfering RNA (siRNA) [115–117] and peptides [118, 119]]. Most importantly, MNP-based drug delivery results in high therapeutic efficacies in both AKI and CKD rodent models. In ischaemic AKI studies [108, 114, 118, 120] and cisplatin-induced AKI models [90, 109, 110, 117], treatment with MNPs causes up to a 100% reduction in kidney disease biomarker levels (creatinine, blood urea nitrogen, KIM-1, neutrophil gelatinase-associated lipocalin, etc.) and tissue injury scores compared with disease and healthy controls. Therapeutic effects specific to individual disease aetiology have been shown in rodent models of unilateral ureteral obstruction (UUO) CKD [111], cisplatin-induced CKD [119], hypertensive CKD [116] and diabetic kidney disease [115]. These promising results in preclinical rodent models portend additional large animal studies and, potentially, clinical trials.

Another kidney-targeting nanoparticle platform with a substantial number of publications is peptide amphiphile micelles (PAMs), with nine research papers published to date [71, 99, 121–127]. PAMs are composed of monomers that have hydrophobic lipid tales and hydrophilic peptide headgroups. The peptide groups [(KKEEE) 3 K peptide] are responsible for the kidney targeting property of PAMs, as they interact with megalin receptors present on tubular epithelial cells and trigger nanoparticle endocytosis. In addition, the diameter of PAMs is <10 nm, which promotes renal accumulation through glomerular filtration [99]. In a biodistribution study, fluorescently labelled PAMs demonstrated ≈35% kidney accumulation out of the total organ fluorescence with approximately equal accumulation in the liver [99]. PAMs have been investigated for kidney-specific drug delivery in a mouse model of autosomal dominant polycystic kidney disease (ADPKD), where they lead to a significant decrease of the cyst index and the kidney weight:body weight ratio [71]. Moreover, PAMs encapsulated into chitosan nanoparticles have been adapted for oral drug delivery with preserved kidney localization and therapeutic efficacy in the ADPKD model [127]. The biodistribution of peptide-modified PAMs was recently evaluated in a one-pig pilot study that demonstrated slightly more accumulation in the kidney than the liver (1.14:1) compared with slightly less for non-targeted micelles (0.81:1) [127]. Continued evaluation of large animal biodistribution and therapeutic efficacy is thus likely to continue.

Another kidney-targeting nanoparticle system that has been tested in non-human primates is single-walled carbon nanotubes (SWCNTs) [128–131]. The initial publication on this system demonstrated that SWCNTs with an average length of 200–300 nm and diameter of ≈1 nm (molecular weight ≈350–500 kDa) are rapidly cleared through glomerular filtration, with some retention in the tubular cells through reabsorption. The glomerular filtration of this material is contradictory to the known glomerular filtration cutoff (30–50 kDa) [128], which was explained by the tendency of flow to orient SWCNTs along the short axis, allowing their passage through glomerular pores [128]. Later, this transport mechanism was explored for targeted delivery of siRNA to the kidneys to treat cisplatin-induced AKI in a mouse model [129]. SWCNT pharmacokinetics and toxicology were evaluated in non-human primates [130], demonstrating that SWCNTs accumulated in the kidneys and liver, with further excretion from these organs, and the toxicological evaluation demonstrated no clinically significant changes [130].

CLINICAL TRANSLATION OF NANOMEDICINES

The pathway to clinical translation is both challenging and imperative. Significant hurdles include the development of extrahepatic targeting nanocarriers and formulation scale-up. Currently the rate of translation from basic research to clinical use is <10% [157, 158]. Engineering challenges also arise, particularly concerning colloidal stability, which may be influenced by factors such as size, contamination and degradation. Careful attention to product development and upscaling is necessary to address the immediate needs of patients with terminal or chronic illnesses [158–160]. For nanomedicines to successfully transition to clinical use, they must comply with Good Manufacturing Practice (GMP) and meet standards for chemistry, manufacturing and control [37] similar to traditional therapeutics. Their effectiveness is contingent upon factors like target accumulation, biodistribution and drug availability [159]. Furthermore, market success relies on obtaining ethical and regulatory approvals and a clear understanding of intellectual property considerations [158, 160].

Before market entry, nanomedicines are required to undergo rigorous clinical trials, which see success rates diminish at each phase [161]. For instance, the success rate for cancer nanomedicines decreases significantly from 94% in phase I to 48% in phase II and only 19% in phase III [162]. A significant factor for these decreases is the physiological differences between humans and animal models, particularly concerning the enhanced permeability and retention (EPR) effect [163]. Theoretically, enhanced permeability is due to ‘leakiness’ of tumour-associated vasculature, while enhanced retention is due to poor lymphatic drainage from the tumour site. This pathophysiologic phenomenon is well-documented primarily in murine solid tumour models [164]. However, while there is some evidence of EPR occurrence in human tumours, it is limited and the presentation varies with patients and tumour types [163, 165, 166]. This underscores the need for preclinical models closely related to human pathophysiology, whether in preclinical cancer studies or other diseases.

To date, ≈100 nanomedicines have been approved by major regulatory agencies, in some cases revolutionizing the diagnosis and treatment of diseases, particularly cancer and infections [167]. The development of these therapeutics is primarily driven by liposomes or lipid nanoparticles, followed by polymers and protein aggregates, with inorganic particles making up a smaller portion [157]. While not engineered nanomaterials, viral vectors, polymer drug conjugates and antibody drug conjugates are examples of closely related biotechnologies that have been approved. As described above, Doxil was the first therapeutic nanomedicine approved by the FDA in 1995, which is a PEGylated liposomal doxorubicin designed to reduce cytotoxicity [168]. Since then, several other nanomedicines—DaunoXome, DepoCyt, Abraxane and Genoxol—have been approved for the treatment of various types of cancer [169]. Among these, Abraxane (nab-paclitaxel) is a blockbuster drug (reaching nearly US$1 billion in sales per year), and it stands out for its unique formulation. Abraxane is composed of human albumin conjugated to paclitaxel and was approved by the FDA in 2005 for the treatment of breast cancer, later expanding to lung cancer in 2012 and pancreatic cancer in 2013 [170]. Currently, nab-paclitaxel is undergoing numerous phase III clinical trials for different tumour indications, including gastric cancer, pancreatic adenocarcinoma and triple-negative breast cancer [27].

Another breakthrough was the approval of Onpattro (patisiran) in 2018, a nanomedicine based on RNA interference that successfully treated hereditary transthyretin-mediated amyloidosis (hATTR), a rare genetic disorder. A major challenge in nucleotide delivery is their degradation, which hinders effective targeting. This issue was addressed by Onpattro, which successfully encapsulated siRNA, protecting it from degradation. Additionally, Onpattro facilitated endosomal escape, ensuring the siRNA was delivered to the cell cytoplasm. The approval of Onpattro marked a significant advancement in nucleic acid–based therapies [171].

The largest blockbusters in the nanomedicine field, and the most well-known, are COVID-19 vaccines, which were developed at an accelerated pace during the 2020 COVID pandemic [161, 172]. Several clinical phases were conducted simultaneously, with significant investments from both the private and public sectors to meet the urgent needs of the population. The Moderna and Pfizer vaccines are lipid nanoparticles that encapsulate mRNA encoding for the severe acute respiratory syndrome coronavirus 2 spike protein. They received FDA approval in 2021 after demonstrating strong immune responses against the virus in preclinical trials involving animals and non-human primates. In the phase II/III trials, both vaccines demonstrated efficacy >90% against the disease, surpassing the FDA's approval criteria, with only mild side effects [172].

Clinically approved nanomedicines for kidney diseases

Given the overwhelming success of nanomedicines in various other facets of human health, nanoparticle-based drug delivery has the potential to significantly improve the treatment of kidney diseases. However, there are hurdles between current preclinical studies and approval, including renal-selective accumulation, i.e. avoiding liver uptake, while preventing renal clearance [44]. To date, there are no FDA-approved nanomedicines that actively accumulate in the kidneys [18]. However, several FDA-approved nanomedicines are effective in improving some symptoms of kidney disease. Iron deficiency is common in patients with CKD. Examples of inorganic nanoparticles that are used to treat CKD-associated iron deficiency include Feraheme (ferumoxytol), Dexferrum and Ferrlecit [44, 167, 173]. Feraheme was approved by the FDA in 2009, as it demonstrated improved efficacy compared with oral iron therapy [174, 175]. Dexferrum and INFed are both iron dextran injections used in patients with iron deficiency when oral administration is not possible, though they are not widely used due to adverse side effects. Ferrlecit, a sodium iron gluconate nanoparticle complex, was launched in 1999 in both adults and paediatric patients who were undergoing haemodialysis. Soon after, Venofer (iron sucrose injection) was indicated for use in certain CKD patients [175]. These iron-replacement therapies are excellent examples of one of the benefits of nanomedicine, improving therapeutic stability and administration despite not demonstrating direct or kidney-selective effects. Additionally, several nanomedicines are currently undergoing clinical trials, with kidney disease or kidney cancer among their applications. One such study uses magnetic nanoparticles coated with human leukocyte antigens to capture donor-specific antibodies in patients with kidney failure [176]. However, there are no apparent ongoing clinical trials relating to kidney-targeting platforms as of May 2025.

PATHS TO THE CLINIC FOR NANOMEDICINES IN NEPHROLOGY

Significant challenges in the clinical translation of all new medicines exist, nanomedicines included, and nanomedicines for nephrology are at the cusp of the translation process. Many promising preclinical candidates fail in the transition to clinical studies, highlighting the need to address these gaps in translation and provide a path forward for the field. Concerns include representative preclinical models, deeper understanding of the formulation's pharmacokinetics, scale-up in manufacturing and clinical trial design. Nanomedicines present unique considerations that may not apply to free active pharmaceutical ingredients due to their size, stability and manufacturing complexity. Below, we outline key factors for successful clinical translation, drawing insights from FDA-approved nanomedicines and translational challenges that have been well-documented in the literature from related fields, while addressing their specific context for kidney-targeting nanomedicines.

Preclinical animal disease models

Animal models are a fundamental part of understanding disease pathophysiology and preclinical testing of novel diagnostics and treatments. Generally the most used animal models in basic biomedical sciences, and kidney nanomedicine specifically, are rodent models. Many rodent models are representative of a variety of kidney diseases, including AKI and CKD [177]. However, there still exist functional and anatomical differences between rodents and humans, which raises concerns about the applicability of these models. Specifically for nanomedicines, these concerns have become increasingly more widespread as many platforms with encouraging preclinical results have not progressed to the clinic [178–180]. As previously mentioned, the lack of a clear EPR effect in humans accounts for many failed translational programs in cancer nanomedicine, underscoring the importance of progressing past rodent disease models prior to the initiation of clinical trials.

With respect to kidneys, preclinical animal models have pitfalls that researchers should be aware of when considering the translatability of results. Differences in kidney function, structure and size across species can influence the absorption, distribution, metabolism and excretion of drugs, which can affect efficacy and toxicity [181]. For instance, inhibition of transforming growth factor-β signalling has slowed the progression of CKD in animal models, yet clinical trials of the therapy have not been fruitful [182]. Large animal models, such as pigs and non-human primates, have renal function and anatomy more similar to humans. However, our evaluation of the literature found just three kidney-targeting nanoparticle systems that have reported data in large animal models (Table 1). This can likely be attributed to kidney-targeting nanomedicines being a relatively new field, where many of these systems have not yet had time to progress to large animal models [17]. Furthermore, renal function may be more similar to that of humans in large animal models, but the complex nature of human kidney disease still cannot be entirely replicated in these models. So, for future success in the field, we stress the need to develop more clinically relevant preclinical models for kidney disease in both small and large animals. Current guidelines for choosing preclinical models, including rodents and in vitro, are published by the International Society of Nephrology [183].

Mechanistic pharmacology

It is also important to understand and be able to explain the pharmacology of each nanomedicine platform. As there are several factors that can influence the biologic fate of nanoparticles, it is integral to not only perform full pharmacokinetic analysis, but also understand the mechanism of action for the cargo and particle. As an iterative discovery process, this may lead to the optimization of nanomedicine platforms in development or further refinement. One common nanomedicine-specific example is their interaction with proteins in blood, which leads to the formation of dynamic coatings of biologic macromolecules on the surface of a nanoparticle. Such protein coronas promote recognition and clearance by the mononuclear phagocyte system (MPS), reducing circulation time and altering biodistribution [184]. Clearance by the MPS can be reduced through certain polymer coatings on the surface of nanoparticles, commonly using polyethylene-glycol (PEG) or zwitterionic polymers [185–187]. A combination of particle size and PEGylation allows for substantial kidney targeting in nanoparticle systems such as mesoscale nanoparticles [93]. Thorough pharmacokinetic analyses are necessary not only for preclinical studies, but to build the body of information in iterative nanomedicine design.

Scale-up in manufacturing

Formulation-specific process development and manufacturing are major hurdles for the translation of nanomedicines [34, 178, 188]. Materials on the nanoscale have unique properties based on their size and surface chemistry. Slight variations in size, shape and surface charge can have great impacts on the functionality of the nanomedicine. In kidney nanomedicines, these factors greatly affect their primary tissue of accumulation [17, 46] (Fig. 2). For this reason, simple designs that allow for precise control over their characteristics are favoured for developing translatable nanomedicines [178]. This includes systems that have fewer components and steps required to synthesize and purify the product. Not only are these systems less complicated in their quality control, but they also tend to be lower in the cost of production, another important factor for translational success. Therefore, it is integral to establish a GMP-compliant manufacturing plan when developing a nanomedicine for the clinic.

New methods have emerged—such as continuous manufacturing and the use of microfluidic devices—to limit variation in large-scale manufacturing. Continuous manufacturing methods allow for scalable production with controlled parameters [189]. The continuous process also typically limits batch-to-batch variability [190], which can often be seen in traditional nanoparticle synthesis. Microfluidic devices improve the control and uniformity of nanomedicine synthesis when compared with other methods [191]. Furthermore, this production method can be successfully scaled up through parallelization [191] or the addition of microfluidic channels. In fact, both the Pfizer-BioNTech and Moderna COVID-19 vaccines utilized microfluidics in their lipid nanoparticle production processes [192]. However, these methods still have room for improvement due to associated challenges, including difficulty replicating complex fluid dynamics, high cost and device clogging [193].

Clinical trial design and regulatory agency collaboration

For many nanomedicines, translation stalls in the clinical trial phase due to safety concerns or insufficient efficacy [157]. Proper clinical trial design may aid in demonstrating the safety and efficacy of nanomedicines over the current standard of care. The field of cancer nanomedicine has progressed many therapies to the clinical trial stage but has seen the success of only a small fraction of these therapies. Consequently, scientists and engineers that design nanomedicines have considered ways to improve translational outcomes [32, 34, 166, 178, 188, 194–196], including the tailoring of clinical trial design. Proper trial design is important to ensure accurate assessment of efficacy and safety, especially in nanomedicines, which have distinct pharmacokinetics and clearance mechanisms. Tailoring suggestions include appropriate definition of endpoints and patient stratification.

Patient stratification allows for the grouping of patients who are most likely to benefit from a particular treatment without severely limiting the size of trial participants. Moreover, it allows for a more tailored approach to treatment based on patient characteristics, such as specific biomarkers or disease stage. Stratification in the context of kidney disease may involve categorizing patients based on factors such as the stage of kidney disease, level of renal function, proteinuria and the presence of comorbidities like diabetes or hypertension. For instance, in patients with reduced kidney function, nanomedicine clearance through the kidneys may be impaired, leading to prolonged circulation times. Or, in patients with increased proteinuria, there may be altered nanoparticle filtration and localization through the glomerulus. These patients may require different dosing strategies to mitigate these risks.

Throughout the clinical design process, it is essential to have meaningful collaboration and contact with clinical scientists and regulatory agencies to improve the chances of approval. Many regulatory agencies echo the recommendation for early-stage collaboration in nanomedicine development, particularly given the varying standards and approval pathways across agencies. Major agencies, including the FDA, the European Medicines Agency, Health Canada and the Japanese Pharmaceuticals and Medical Device Agency, have published some initial guidance for nanomedicines but continue to evaluate these products within their existing frameworks [197]. Recently, the European Union funded the REFINE project, which developed a Decision Support System to help advance promising nanomedicine candidates to the clinic by supporting preclinical safety testing [198]. As countries continue to develop and expand their nanomedicine regulation strategies in response to the growing market, it is essential for developers to stay up to date with the latest guidance.

Industry collaboration and development

Developing a new therapeutic drug and bringing it to market is associated with high risk and cost [199], which is a major reason why most clinical trials are industry-funded [200]. To our knowledge, no large pharmaceutical or biotechnology companies have made significant investments into kidney-targeting nanomedicines. There are several start-up companies in this space, primarily stemming from academic lab spinoffs. Many of the considerations for kidney-targeting nanomedicines are costly, and progression to clinical trials may depend on or benefit from collaboration with industry sources. This financial support could help advance research into costlier large porcine and non-human primate models, support manufacturing scale-up and enhance regulatory engagement.

High development costs of new therapeutics, including nanomedicines, often result in significantly elevated prices for patients and healthcare providers, which can hinder the clinical adoption of these technologies. This is not to say that the cost to manufacture or develop a nanomedicine is inherently higher than others, just that new therapeutic modalities are often costly. This is especially true if nanomedicines are developed in a personalized or patient-tailored manner (e.g. targeting specific mutations, etc). Kidney-targeting nanomedicines must strike a balance between their cost and anticipated benefits to prevent restrictions in their implementation. Industry collaboration and regulatory agencies can play a substantial role in this. Related to the cost, the time it takes to translate technologies to the clinic is substantial, especially considering none are currently in clinical trials. Overall, collaboration between academia and industry will help pave the way for more clinical nanomedicine advancement.

Future directions and conclusions

The prevalence and morbidity associated with acute and chronic kidney diseases highlight the need for improved diagnostic and therapeutic strategies. Kidney-targeting nanomedicines have the potential to improve kidney disease treatment and diagnostics by delivering therapeutics directly to the site of kidney injury. However, nanomedicines face many barriers for entry to the clinic, so it is crucial to address these common problems to ensure kidney-targeting nanomedicines have an optimal impact on patient outcomes. Reviewing the paths of previously successful nanomedicines and recommendations given to other fields, we identified several essential elements to improve when translating from bench to bedside, illustrating the proposed translational timeline (Fig. 3) and highlighting future research avenues to be explored (Table 2). By refining preclinical models, understanding nanoparticle pharmacokinetics and tailoring clinical trial designs, kidney-targeting nanomedicines hold great promise for revolutionizing the diagnosis and treatment of kidney diseases. We are confident that a streamlined, team-based, patient-focused approach to clinical development of kidney-targeted nanomedicines will increase the likelihood of success and ultimately facilitate more rapid translation to the clinic. Translational efforts will not only work to support individual success, but will also open the door for more kidney-targeting nanomedicine products in the future.

Figure 3:

The roadmap for clinical translation for kidney-targeting nanomedicines and ways to address potential roadblocks along the way.

Table 2:

Future research recommendations for kidney-targeting nanomedicines.

Future research directions	Goal(s)	Rationale
Disease-specific models	Collaboration of nanomedicine developers, disease biologists and clinicians to utilize the most effective preclinical models	Tailored and representative models better predict clinical outcomes, improving translational likelihood [177, 181, 183]
Genomic therapies	Improve delivery of RNA-based or CRISPR therapeutic agents to the kidney	Substantial in vitro work has been done to develop genomic therapies, although these are difficult to translate in vivo [66]
Manufacturing and reproducibility	Enhance manufacturing methods of kidney-targeting nanomedicines for reduced cost and high reproducibility	Scalable and reproducible manufacturing methods are necessary during translation [34, 178, 188]
Improve renal targeting	Develop and optimize methods to increase kidney targeting and to selectively localize particles to cells within the kidney	Understanding targeting methodologies, including active and passive methods, can improve accumulation in target tissues and cell types, potentially improving therapeutic responses and limiting off-target interactions [201]
Diagnostic and theranostic development	Design nanomedicines that combine therapeutics and diagnostics for kidney disease in one platform	Integration of diagnostic methods with therapeutic agents can allow for real-time monitoring of disease progression and treatment response [37]
Personalized treatment	To facilitate the delivery of highly selective treatments based on a patient's mutations or disease history	Personalized treatment, based on disease type, genetics and severity, can improve patient outcomes, as progression of kidney diseases can affect the accumulation of nanoparticles
Degradation and safety	Ensure systems are cleared from the body to reduce long-term toxicity and understand mechanisms of clearance or degradation	Understanding particle degradation, whether by intact renal clearance or degradation, is necessary for long-term safety [38, 39]
Pharmacokinetic analysis	Understand the pharmacology of current kidney-targeting nanomedicine platforms to optimize	Pharmacokinetic analysis can inform design parameters and dosing strategies to optimize the therapeutic efficacy of the nanomedicine and ensure towards-the-clinic development

FUNDING

This work was supported by the National Institute on Minority Health and Health Disparities of the National Institutes of Health (award no. U54MD017979). Z.S. was supported by the Department of Education Research and Development Infrastructure (award no. P116H230008). EAJ was supported by P30 CA008748 and RO1 DK129299.

DATA AVAILABILITY STATEMENT

No new data were generated or analysed in support of this research.

CONFLICT OF INTEREST STATEMENT

R.M.W. is the founder of Zipcode Therapeutics.