Kidney-Targeting Drug Delivery Systems for Chronic Kidney Disease

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INTRODUCTION Chronic kidney disease (CKD) is a major condition characterized by persistent impairment of kidney function and structure, affecting over 800 million individuals worldwide (> 10% of the global population).[1,2] Although antihypertensive and antihyperglycemic agents can delay the decline of kidney function to some extent, the clinical therapies for end-stage renal disease resulting from CKD are still limited to dialysis and kidney transplantation, which are costly and non-curative.[1] Therefore, developing novel therapies for CKD is essential. To address these limitations, enhance therapeutic efficacy, and reduce systemic toxicity, nanotechnology-based targeted drug delivery platforms have emerged as a promising strategy [Figure 1]. Through sophisticated structural and surface engineering, nanocarriers enable precise delivery to renal tissues and cells via size- and charge-mediated passive targeting,[3-5] as well as active recognition mechanisms utilizing targeting ligands and biomimetic nanocarriers.[6-10]Figure 1.: Passive and actively kidney-targeting pathways of nanoparticles. GFB, glomerular filtration barrier; FA, folic acid; KIM-1, kidney injury molecule 1; HDL, high-density lipoprotein. GFB, glomerular filtration barrier.In addition, the integration of nanotechnology further enables multifunctionality in renal-targeted drug delivery systems [Figure 2], including stimuli-responsive drug release and combination therapy.[4,5,7,8,10] These advances offer a robust platform for developing highly effective and low-toxicity treatments for renal fibrosis—a critical clinical challenge for which specific therapeutics are still lacking.[2] Herein, we systematically analyze the structural basis of renal-targeted drug delivery systems and demonstrate their considerable potential for enhancing therapeutic efficacy in CKD.Figure 2.: The functions of kidney-targeting nanoplatforms include stimuli-responsive drug release and combination therapy. ROS, reactive oxygen species; STING, stimulator of interferon genes; PD-1, programmed cell death protein 1; PD-L1, programmed cell death ligand 1. TP, Triptolide; BIBF, Nintedanib.NANOPARTICLE-BASED DRUG DELIVERY FOR CHRONIC KIDNEY DISEASE The treatment of CKD is hampered by complex disease mechanisms, inadequate drug targeting, systemic side effects, and poor renal tissue penetration.[2] Nanoparticles are materials with at least one dimension below 100 nm that can be engineered for kidney targeting through tailored size, surface charge, ligand modification, and biomimetic strategies.[1] Nanocarriers can protect drugs from degradation and premature clearance, enhancing delivery to pathological sites.[1,2] Furthermore, they serve as ideal platforms for combination therapy, simultaneously carrying anti-inflammatory or antifibrotic agents to enable synergistic treatment,[1] thereby addressing fundamental limitations in CKD therapy. PASSIVE KIDNEY-TARGETING NANOPLATFORMS Kidney-targeting nanocarriers access distinct renal compartments depending on their size, which directly influences the efficacy of passive targeting.[1] Nanoplatforms smaller than the glomerular filtration barrier (GFB) Nanoparticles conforming to the typical cutoff size (< 10 nm) traverse the glomerular barrier, accessing glomerular and tubular cells as they pass through the tubules, thereby enabling treatment of tubulointerstitial fibrosis.[3,4,6] Although the rapid renal clearance of ultrasmall nanomaterials (< 5-6 nm) limits their therapeutic utility,[5,6] ultrasmall nanoclusters (< 1.2 nm) can effectively treat CKD via systemic reactive oxygen species (ROS) scavenging.[3] Furthermore, nanoplatforms at approximately 7 nm strike a balance between rapid clearance and sufficient retention; they are partially eliminated to reduce systemic exposure and potential toxicity, yet retain adequate concentration at pathological sites to exert therapeutic efficacy.[6] Nanoplatforms larger than the GFB Nanoparticles larger than 20 nm cannot pass through the GFB, but they can still reach the kidney via the circulatory system.[1] Larger nanoparticles (around 45 nm) exhibit high and sustained accumulation in the spleen and liver, primarily due to increased uptake by the mononuclear phagocyte system, a fate distinct from that of ultrasmall nanoclusters.[3] Nanoparticles within the range of 75 nm ± 25 nm have been shown to target mesangial cells within the glomerular compartment to exert antifibrotic effects.[7] The size range of 100-200 nm has also been demonstrated to facilitate nanoparticle extravasation through vascular endothelial gaps in the kidney and to promote enrichment within fibrotic areas.[1] Furthermore, cationic mesoscale nanoparticles (350-400 nm) have been proven to selectively accumulate in proximal tubular epithelial cells, with up to sevenfold higher efficiency in the kidney than in other organs.[1] ACTIVELY KIDNEY-TARGETING NANOCARRIERS To address the limited targeting efficiency of passive approaches, more precise active targeting strategies have been developed. Ligand-dependent kidney-targeting nanoplatforms The surface modification of nanocarriers with specific ligands enables precise drug delivery to distinct renal cell types.[1] Notably, nanocarriers that specifically recognize and bind to KIM-1 facilitate targeted delivery to damaged renal tubular epithelial cells.[1,10] Additionally, folic acid binds to folate receptors overexpressed on the apical membrane of tubular epithelial cells, leading to substantial enrichment in diseased kidneys.[6] The targeting ligand BMS-α specifically recognizes the melanocortin-1 receptor, which is highly expressed on podocytes in diabetic nephropathy models.[7] Biomimetic-based kidney-targeting nanoplatforms Biomimetic camouflage, such as cell membrane coating, enhances the biocompatibility and immune evasion capacity of nano-delivery platforms.[7,9] Concurrently, membrane proteins (e.g., αV integrin) facilitate homotypic adhesion to renal cells, enabling kidney-specific accumulation.[8] Biomimetic nanoplatforms also exhibit prolonged circulation due to their structural resemblance to native biomolecules, and they naturally target kidney-associated receptors through functional mimicry.[10] More recently, biomimetic nanorobots have been applied to renal-targeted delivery. They utilize flagellar propulsion from integrated microalgae to navigate autonomously to glomerular and interstitial sites, overcoming limited drug penetration in kidney diseases.[9] Therefore, the development of biomimetic nanoplatforms has undoubtedly provided new momentum for the design of kidney-targeting drug delivery systems. KIDNEY-TARGETING NANOPLATFORMS FOR CKD TREATMENT Nanoparticle-based drug delivery systems enable stimuli-responsive drug release through sophisticated design and facilitate combination therapy via the co-loading of multiple agents. Stimuli-responsive drug release The stimuli-responsive behavior of nanoplatforms relies on specific structural designs, which can be realized through cleavage of covalent bonds in inorganic frameworks,[4,5] disintegration of membrane components,[7] or the incorporation of stimuli-responsive moieties to enable externally triggered drug release.[9] Capitalizing on the acidic microenvironment of pathological sites, nanoplatforms are engineered with pH-responsive structures to achieve site-specific drug release.[5,7] In addition, the elevated ROS levels characteristic of inflammatory milieus in kidney diseases are exploited as triggers for smart responses.[4] Emerging strategies also involve the integration of magnetic nanoparticles, which allow precise navigation and spatiotemporally controlled drug release under external magnetic guidance.[9] Combination therapy Combination therapy and multi-mechanistic treatment represent key advantages of nanoplatforms in enhancing therapeutic efficacy against CKD. These nanoplatforms have been demonstrated to effectively co-load anti-inflamm

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