Nanomedicine-Driven Precision Therapy for Renal Fibrosis: From Mechanistic Insights to Kidney-Targeted Interventions

Abstract

Renal fibrosis acts as the convergent and irreversible pathological endpoint driving chronic kidney disease (CKD) to end-stage renal disease. Characterized by aberrant extracellular matrix (ECM) deposition and parenchymal architecture disintegration, this process is orchestrated by a dynamic multicellular network involving myofibroblast activation, metabolic reprogramming, and intricate crosstalk among signaling hubs like TGF-β/Smad and Wnt/β-catenin. While cornerstone therapies, such as renin-angiotensin system inhibitors (RASI) and sodium-glucose cotransporter 2 (SGLT2) inhibitors, retard progression, they face significant bottlenecks, notably the inability to reverse established fibrosis and the risk of off-target systemic toxicity. Nanomedicine offers a precision-engineering approach to surmount these physiological barriers. By leveraging spatiotemporal control, intelligent nanocarriers facilitate kidney-targeted delivery and microenvironment-responsive release, while functional nanomaterials exert intrinsic antioxidative and anti-fibrotic bioactivity to reshape the fibrotic niche. This review systematically delineates the molecular landscape of renal fibrosis—with particular attention to emerging drivers such as epigenetic regulation and ferroptosis—and critically examines the translational hurdles of current strategies. Integrating molecular insights with nanotechnological innovation, we discuss how nanomedicine can potentiate therapeutic efficacy and enable phenotype-specific precision interventions. Finally, we provide a forward-looking perspective on overcoming clinical barriers and constructing integrated theranostic and regenerative platforms.

Introduction

Chronic kidney disease (CKD) has evolved into a global public health crisis, characterized by its staggering prevalence and escalating socioeconomic impact. According to the Global Burden of Disease Study 2021 and recent authoritative updates, CKD currently affects over 850 million individuals worldwide—surpassing 10% of the global population.^1,2 Alarmingly, predictive models indicate that CKD is on a trajectory to become the 5th leading cause of death globally by 2040.³ This rising prevalence imposes a formidable economic burden; direct healthcare expenditures, driven primarily by the need for renal replacement therapies, encompassing dialysis and transplantation, are projected to surge precipitously, placing an unsustainable strain on global healthcare systems.⁴ Central to this clinical dilemma, however, is the pathological mechanism of renal fibrosis. Serving as the final common pathway for the progression of CKD to end-stage renal disease across diverse etiologies, renal fibrosis is defined by aberrant extracellular matrix (ECM) deposition and the disintegration of renal parenchymal architecture.² It is this progressive and often irreversible fibrotic process that inexorably precipitates the loss of renal function, rendering it a critical bottleneck for effective clinical intervention.

CKD commonly arises in the context of overlapping risk factors and comorbidities rather than a single isolated process. Diabetes and hypertension remain the leading causes worldwide, but obesity, aging, recurrent acute kidney injury, and nephrotoxic exposures also contribute to distinct fibrotic trajectories.^1,2,5 These clinical contexts are therapeutically relevant because several upstream drivers are modifiable before scarring becomes advanced. Examples include metabolic and mineralocorticoid signaling in diabetic kidney disease and the endothelin, renin-angiotensin, and mucosal immune pathways targeted in IgA nephropathy.^2,6–11 Framing CKD in this way can guide nanotherapeutic design, including the choice of targeting ligand, payload, and release mechanism for the dominant disease context.

The pathophysiology of renal fibrosis is driven by a highly heterogeneous multicellular network, which, while offering abundant cellular targets, imposes significant challenges for precise intervention. Damaged tubular epithelial cells (TECs) act not merely as victims but as active drivers of fibrogenesis through G2/M phase arrest and the secretion of pro-inflammatory mediators; however, selectively eliminating these senescent cells without compromising healthy tubular regeneration remains a formidable hurdle.^12,13 Simultaneously, myofibroblasts (MYFs), serving as the principal executors of collagen deposition derived from diverse lineages, necessitate therapeutic strategies capable of selectively recognizing activated phenotypes while preserving physiological interstitial homeostasis.¹⁴ Furthermore, complex immune dysregulation, exemplified by the dynamic imbalance of M1/M2 macrophage polarization and the formation of neutrophil extracellular traps (NETs), underscores the inadequacy of generic immunosuppression, thereby highlighting the urgent need for intelligent delivery strategies capable of in situ “immune reprogramming” to disrupt the vicious cycle of inflammation and fibrosis.^15,16 In the realm of molecular signaling, the TGF-β/Smad axis functions as a central regulatory hub, engaging in extensive crosstalk with the Wnt/β-catenin and Notch pathways to coordinate ECM production and pericyte transdifferentiation.^17,18 At the metabolic and matrix tiers, mitochondrial dysfunction and the aberrant activation of cross-linking enzymes—coupled with the inhibition of matrix metalloproteinases—collectively precipitate matrix stiffening and microvascular rarefaction.^19,20 Consequently, the intricate pathogenesis of renal fibrosis can be synthesized into four principal dimensions, as illustrated in Figure 1: synergistic multicellular interactions fostering a pro-fibrotic inflammatory microenvironment; the hyperactivation of core signaling networks; the profound disruption of ECM homeostasis; and the convergence of epigenetic regulation with mitochondrial dysfunction.

Figure 1.

Schematic illustration of the core pathogenic mechanisms of renal fibrosis and the paradigm of nanomedicine-based intervention. The diagram delineates the pathogenesis of renal fibrosis across four interrelated dimensions: multicellular interactions culminating in a pro-fibrotic inflammatory microenvironment; the activation of pivotal signaling pathways driving fibrotic progression; the disruption of extracellular matrix (ECM) homeostasis; and epigenetic regulation coupled with mitochondrial dysfunction. The fibrotic kidney is centralized, encircled by a Corona of nanoparticles, symbolizing the integration of mechanistic insights with targeted nanotherapeutic strategies. Symbol legend: Black arrows indicate biological promotion or pathway activation; blunt-ended lines indicate inhibition or blockade; red upward (↑) and downward (↓) arrows denote an increase in ECM deposition and a decrease in ECM degradation, respectively; colored circles and the flame symbols within the microenvironment represent pro-fibrotic and inflammatory factors, respectively.

Although cornerstone therapeutic approaches, including renin-angiotensin system inhibitors (RASI) and sodium-glucose cotransporter 2 (SGLT2) inhibitors, function to retard the progression of CKD, current treatment strategies for renal fibrosis are constrained by three critical hurdles. The primary limitation is the inability to regress established fibrosis. While existing pharmacotherapies may attenuate fibrogenesis, they fail to reverse the accumulated scar tissue; notably, monoclonal antibodies targeting key mediators such as TGF-β or connective tissue growth factor (CTGF) have failed to achieve primary efficacy endpoints in Phase II clinical trials, likely owing to the activation of compensatory signaling cascades.^6,21 The second impediment lies in the dilemma of insufficient drug specificity and poor delivery efficiency. The clinical utility of broad-spectrum tyrosine kinase inhibitors, such as pirfenidone, is compromised in renal indications by dose-limiting systemic toxicities and suboptimal renal tropism.²² Compounding this is the dense, cross-linked ECM within fibrotic lesions, which acts as a formidable physical barrier restricting the perfusion and deep penetration of conventional small-molecule therapeutics. This physical limitation stands in stark contrast to the capabilities of nanomedicine, where carriers can be engineered to breach this barrier and achieve deep lesion penetration.²³ The third critical hurdle is the profound translational gap between mechanistic insights and clinical application. Conventional preclinical models frequently fail to recapitulate the complex microenvironmental heterogeneity of human CKD. Furthermore, the pleiotropic nature of therapeutic targets and the absence of molecularly guided patient stratification continue to hinder the successful translation of anti-fibrotic interventions.^23–25

Herein, this review aims to systematically elucidate the intricate molecular mechanisms governing renal fibrosis, while providing a critical appraisal of the full spectrum of therapeutic strategies—ranging from foundational pharmacotherapies to the vanguard of nanomedicine. Crucially, distinct from existing reviews that often compartmentalize material science and disease pathology, this article uniquely bridges the gap between molecular insights and nanocarrier engineering, proposing a mechanism-guided framework for precision intervention. Specifically, we analyze how recent breakthroughs in nanoparticle design—leveraging spatiotemporal control and intrinsic bioactivity—can dismantle specific therapeutic bottlenecks, such as the dense ECM barrier and systemic toxicity. Finally, we delineate the formidable translational challenges and provide a forward-looking perspective on constructing integrated theranostic and regenerative platforms to propel this interdisciplinary field forward.

Mechanisms of Renal Fibrosis

Multicellular Interactions

Myofibroblasts—The Core Effectors of Fibrosis

MYFs function as the principal executioners of aberrant ECM deposition, possessing a hybrid phenotype that combines the collagen-synthesizing machinery of fibroblasts with the contractile mechanics of smooth muscle cells. Phenotypically, these cells are distinguished by the expression of alpha-smooth muscle actin (α-SMA) and the assembly of contractile stress fibers. Throughout the progression of CKD, MYFs originate from diverse differentiation lineages and display profound functional heterogeneity, thereby establishing the cellular foundation of renal fibrosis¹⁴ (Figure 2).

Figure 2.

Multicellular interactions and major sources of myofibroblasts in renal fibrosis. This schematic illustrates the diverse origins of myofibroblasts—the core effector cells in renal fibrosis—and highlights the contributions of various immune and stromal cells in shaping a pro-fibrotic microenvironment. The principal pathways generating myofibroblasts include macrophage-to-myofibroblast transition (MMT), endothelial-to-mesenchymal transition (EndoMT), and epithelial-to-mesenchymal transition (EMT), which are largely driven by the TGF-β/Smad signaling axis. Furthermore, immune cells such as M1 and M2 macrophages, neutrophils, CD8⁺ T cells, and Th17 cells release a spectrum of fibrogenic mediators, encompassing IL-17A, granzyme B (GZMB), and the CXCL chemokine family, which collectively exacerbate inflammatory responses, stimulate extracellular matrix (ECM) deposition, and ultimately propel the progression of renal fibrosis. Symbol legend: Bold black arrows indicate cell differentiation; thin solid black arrows represent biological promotion or pathway activation; thin dashed black arrows denote cellular recruitment; red upward (↑) and downward (↓) arrows signify an increase or decrease in molecular expression or environmental factors, respectively.

Quiescent fibroblasts (PDGFRα⁺ PDGFRβ⁺) constitute one of the primary sources of MYFs, undergoing transdifferentiation into α-SMA⁺ collagen-secreting MYFs following stimulation by the TGF-β/Smad signaling axis.¹⁷ Recent single-cell transcriptomic analyses have further unveiled the profound functional heterogeneity inherent to these populations. Distinct subpopulations are biologically committed to ECM synthesis and deposition, whereas others specialize in migratory capacity or contractile mechanics.¹⁴ In this context, guanylate cyclase 3 has been delineated as a pivotal modulator of MYF contractility, with specific inhibitors demonstrating efficacy in attenuating tissue tension within fibrotic models.

Pericytes (PDGFRβ⁺ NOTCH3⁺ NG2⁺) possess the latent potential to transdifferentiate into MYFs following dissociation from the capillary endothelium, a process that destabilizes vascular integrity and precipitates microvascular rarefaction.²⁶ However, the precise magnitude of their contribution remains a subject of intense debate. Contemporary consensus suggests that under specific microenvironmental cues—notably TGF-β and hypoxia—a subset of pericytes undergoes transdifferentiation, thereby perpetuating the vicious cycle between microvascular rarefaction and hypoxic injury.^26,27

Beyond resident populations, the expansion of the MYF pool is significantly fueled by the transdifferentiation of bone marrow-derived macrophages (a process known as macrophage-to-myofibroblast transition (MMT) and endothelial-to-mesenchymal transition (EndoMT).¹⁵ Given their diverse origins yet convergent phenotype, identifying surface markers specific to activated MYFs—rather than quiescent fibroblasts—remains a critical objective for designing ligand-functionalized nanocarriers to achieve precision targeting.

Reprogramming of Intrinsic Renal Cells in Fibrosis

Renal Tubular Epithelial Cells

TECs serve as both primary targets of injury and active drivers in the pathogenesis of renal fibrosis. Post-injury, these cells undergo profound dedifferentiation characterized by cell cycle arrest at the G2/M checkpoint, phenotypic transformation manifesting as partial epithelial-to-mesenchymal transition (EMT), and the acquisition of a senescence-associated secretory phenotype. These senescent-like cells stimulate stromal fibroblasts by orchestrating excessive ECM accumulation via the release of profibrotic mediators including TGF-β, Wnt, and ET-1.^13,28–30

Notably, cell death modalities play a crucial role in amplifying inflammation. Pyroptosis, activated through Caspase-1/GSDMD and Caspase-3/GSDME pathways, releases IL-1β and IL-18 to recruit neutrophils.^31,32 Furthermore, ferroptosis—a form of regulated cell death driven by GPX4 inactivation and consequent lipid peroxidation—has emerged as a key pathogenic driver of renal fibrosis.^33–35 Mechanistically, impaired function of the cystine/glutamate antiporter (System Xc-) leads to glutathione depletion and the subsequent inactivation of GPX4, a critical lipid repair enzyme, alongside the upregulation of ACSL4. This process not only instigates tubular cell loss but also propagates inflammation via NOX4-induced oxidative stress and TXNIP activation, while the release of damage-associated molecular patterns activates neighboring fibroblasts to establish a pro-inflammatory feed-forward loop. Notably, the druggability of ferroptosis pathways—with a particular focus on GPX4 and system Xc-—presents a strategic entry point for antioxidant-based nanotherapeutics. For instance, engineered selenium-based nanomaterials have been demonstrated to convert into bioactive GPX4 enzymes in situ, thereby specifically mitigating lipid peroxidation and arresting the fibrotic cascade.³⁶

Mesangial Cells

In diabetic kidney disease (DKD), mesangial cells (MCs) acquire a myofibroblastic phenotype and excessively deposit ECM proteins, leading to glomerulosclerosis. This activation is driven by complex transcriptional networks, including the transcription factor GABP, which targets the GLI1 promoter to sustain proliferation. Crucially, MC activation is regulated by the intersection of the TGF-β/CTGF axis and Wnt/β-catenin signaling, where TGF-β1 induces CTGF to facilitate collagen cross-linking via integrin αvβ3. Targeting these activated MCs within the glomerulus requires nanocarriers engineered with specific size and charge properties to traverse the fenestrated endothelium while avoiding rapid clearance.^30,37

Endothelial Cells and Pericytes

Injury to vascular endothelial cells precipitates capillary rarefaction, creating a hypoxic milieu that exacerbates microvascular compromise and drives endothelial apoptosis.^26,38 Concurrently, pericyte detachment destabilizes the basement membrane architecture, establishing a pathogenic feed-forward loop wherein hypoxia, tubular injury, and fibrosis synergistically propagate one another. Furthermore, pericyte transdifferentiation not only directly instigates microvascular rarefaction and tissue hypoxia but also actively fuels fibrotic progression by engaging TGF-β1 signaling cascades.^26,39 This highlights the potential for nanomedicine strategies that co-deliver angiogenic factors and anti-fibrotic agents to simultaneously restore vascular integrity and halt pericyte transition.

Immune Cells—The Bridge Between Inflammation and Fibrosis

Macrophages

The dysregulated equilibrium in M1/M2 macrophage polarization functions as a pivotal determinant in the initiation and progression of renal fibrosis. Classically activated M1 macrophages, stimulated by cytokines, typified by TNF-α and IFN-γ, exhibit high expression of inducible nitric oxide synthase (iNOS) and release pro-inflammatory mediators including IL-6, IL-12, and TNF-α, thereby exacerbating tubular injury and oxidative stress responses. Conversely, pro-fibrotic M2 macrophages secrete TGF-β, PDGF, and galectin-3. By orchestrating the Smad3 and MAPK signaling cascades, they promote the transdifferentiation of fibroblasts into MYFs, directly driving ECM deposition.^15,40 Recent evidence indicates that TSC1 gene loss potentiates MMT via mTORC1 hyperactivation, generating collagen-secreting CD68⁺/α-SMA⁺ effector cells.⁴¹ Consequently, nanocarriers capable of repolarizing M2 macrophages back to a non-fibrotic phenotype represent a promising “immune reprogramming” strategy.⁴²

Neutrophils and CD8+ T Cells

Renal tissue ischemia or obstruction instigates PAD4-dependent histone citrullination, which is marked by CitH3, precipitating the release of NETs composed of DNA-protein complexes.^43,44 Clinical investigations reveal that elevated serum CitH3 and dsDNA levels in patients with renal fibrosis exhibit a significant inverse correlation with the estimated glomerular filtration rate (eGFR). Mechanistically, these NETs activate macrophages via the TLR2/4 signaling axis, inducing the secretion of chemokines, notably CXCL9/10/11, which subsequently orchestrate CD8⁺ T cell infiltration into the kidney. Once recruited, CD8⁺ T cells propel EMT in TECs—characterized by the repression of E-cadherin and upregulation of vimentin—through the secretion of granzyme B (GZMB), whilst concurrently driving fibroblast activation.⁴³

Other Immune Cells

Th17 Cells—Key Effectors in Inflammatory Amplification

Th17 cells constitute a pivotal immune subset that orchestrates the inflammatory cascade driving renal fibrosis, a process regulated by intricate signaling networks. Injured TECs actively promote the recruitment of inflammatory monocytes and Th17 cells to the renal parenchyma by upregulating pro-fibrotic mediators such as Zeb2 and Pdgfb. Once established within fibrotic foci, Th17 cells directly activate MYFs via the secretion of IL-17A, thereby facilitating the establishment of fibrotic niches. Concurrently, they stimulate TGF-β1 release and propel EMT, thus accelerating fibrogenesis. Moreover, Th17 cells potentiate renal inflammation and ECM remodeling through sustained IL-17A production. In experimental models, the depletion of Th17 cells—achieved via mTOR inhibition or suppression of differentiation—significantly attenuates disease severity. Crucially, the perturbation of immune homeostasis, specifically the disequilibrium of the Th17-to-Treg ratio, exacerbates tissue injury; this aligns with clinical observations where an elevated Th17/Treg ratio correlates positively with the progression of nephropathies.⁴⁵

Fibrocytes—Bone Marrow-Derived Matrix Producers

Fibrocytes represent a distinct cell population characterized by a chimeric phenotype, exhibiting dual properties of both immune cells and fibroblasts, and actively engaging in ECM deposition and tissue remodeling during renal fibrosis. Mobilised by injury signals—notably SDF-1 and PDGF—bone marrow-derived CD34⁺ progenitors migrate to the renal parenchyma via chemokine receptor-mediated homing.¹⁴ Upon infiltration, these cells differentiate to highly express type I/III collagen, FN1, and MMP-2/MMP-9, thereby directly fueling matrix accumulation. Concurrently, they act as paracrine hubs, secreting CTGF and PDGF-BB to orchestrate the transdifferentiation of resident fibroblasts into α-SMA⁺ MYFs.

Immunologically, fibrocytes facilitate inflammatory crosstalk via the CD40-CD40L costimulatory axis. This pathway potentiates the interaction between T cells—potentially including the Th17 subset—and myeloid-derived cells, establishing a positive feedback loop that perpetuates pro-inflammatory and pro-fibrotic responses.⁴⁶ Interrupting these immune cell-fibroblast communication axes using targeted nanomedicine offers a novel avenue to dampen the inflammatory microenvironment.²

Microenvironment Reconstruction

Dynamic Remodeling of the Extracellular Matrix

During renal fibrosis, the ECM transitions from a structural support to a driver of signal dysregulation. Key to this is the excessive deposition of collagen types I, III, and IV, alongside adhesive glycoproteins like FN1. The stability of this pathological matrix is fortified by cross-linking enzymes such as TG2 and LOXL2, which mediate collagen stiffening. The resulting dense, cross-linked ECM not only drives mechanotransduction signaling but also creates a steric physical barrier, highlighting the necessity for size-tunable nanocarriers to achieve deep tissue penetration.^19,47

Oxidative Stress Microenvironment

The oxidative stress microenvironment constitutes a pivotal mechanism governing fibroblast activation. The deficiency of GPX3 in TECs triggers a chain reaction that establishes a self-amplifying oxidative cycle. As a key antioxidant guardian, GPX3 primarily mediates the detoxification of peroxides to preserve redox balance. Reduced GPX3 expression diminishes the capacity for extracellular H₂O₂ clearance, enabling interstitial fibroblasts to sense oxidative damage signals. This event subsequently activates NOX4 and drives the production of reactive oxygen species (ROS), which further exacerbates the oxidative milieu and stimulates fibroblast expansion. NOX4 plays an integral role in the ROS/PKCα/MAPK signaling axis during renal fibrosis. ROS generated via this pathway activate PKCα, which promotes MAPK phosphorylation and drives the nuclear translocation of STAT3. This ultimately induces the expression of markers associated with fibroblast proliferation and myofibroblast transition. Experimental evidence confirms that silencing NOX4 reduces MAPK phosphorylation and α-SMA levels, effectively inhibiting fibroblast activation and renal fibrosis.^19,20,48

Formation of Fibrotic Niche

The fibrotic niche represents a specialised, maladaptive ecosystem situated at sites of focal injury. Within this milieu, activated MYFs, immune cells, and apoptotic TECs interact within a stiffened ECM scaffold. This niche is anchored by oxidative stress and further compounded by hypoxia-induced HIF-1α upregulation. Single-cell spatial transcriptomics have elucidated a “core-periphery” zonal pattern: a fibrotic core characterized by vascular rarefaction and a peripheral active signaling front.² Targeting this dynamic niche requires “smart” nanocarriers with spatiotemporal responsiveness to specific microenvironmental cues, such as hypoxia or acidic pH.^19,47

Core Signaling Networks and Metabolic Reprogramming

Synergistic Effects in Core Signaling Pathways

The TGF-β/Smad signaling pathway acts as a pivotal hub in renal fibrosis, driving disease progression through diverse mechanisms ranging from altered ECM metabolism and the induction of EMT to the promotion of inflammation.¹⁷ This pathway upregulates ECM synthesis-related genes while suppressing matrix degradation processes; simultaneously, it induces EMT in TECs through TGF-β/Smad-dependent signaling and stimulates the release of pro-fibrotic factors, creating a vicious cycle linking inflammation and fibrosis. Additionally, TGF-β signaling incorporates autoregulatory negative feedback, employing effectors like Smad3 to sustain Smad7 transcription and limit excessive activation. Notably, recent studies have further elucidated the upstream transcriptional network of this pathway. For example, Klf6 functions as a key regulator by binding directly to the Smad3 promoter to enhance its transcription, thereby forming a Klf6-Smad3 axis that accelerates fibrosis⁴⁹ (Figure 3). This mechanism highlights a promising target for therapeutic intervention.

Figure 3.

The Klf6-Smad3 axis in renal fibrosis and its inhibition by biochanin A. The schematic illustrates that TGF-β signaling induces Klf6 expression, which in turn activates Smad3 transcription, driving renal fibrosis. Biochanin A attenuates fibrosis by suppressing Klf6, thereby downregulating Smad3 and disrupting the pro-fibrotic cascade. Reproduced from Li et al, 2024⁴⁹ with permission from Phytomedicine.

The Wnt/β-catenin pathway exhibits a “double-edged” characteristic in renal fibrosis, contributing to both physiological repair and pathological scarring.^17,30 Activation of this pathway triggers β-catenin nuclear translocation, upregulating genes such as TGF-β1 and Snail1. This process facilitates MCs activation and tubular EMT, leading to the accumulation of α-SMA⁺ MYFs. Furthermore, this pathway engages in extensive crosstalk with TGF-β, jointly driving fibrotic progression.

The Notch pathway regulates critical paracrine signaling between peritubular cells and endothelial cells.^18,50 In response to renal injury, endothelial cells abnormally express the Jagged1 ligand, activating Notch3 receptors on peritubular cells. This induces their detachment from microvascular structures and subsequent transformation into α-SMA⁺ MYFs. This transdifferentiation process compromises microvascular stability, triggering local hypoxia that activates the HIF-1α/TGF-β axis and intensifies fibrosis.¹⁸

In summary, while MYFs represent the core effector cells in renal fibrosis, their fate is regulated by a complex interactive network rather than isolated pathways. Signaling cascades such as TGF-β/Smad, Wnt/β-catenin, and Notch operate synergistically. Within this network, critical signaling nodes—including TGF-β1, mTOR, ROS, PI3K/Akt, and STAT3—serve as the central engines of myofibroblast activation.^27,41 Deeply understanding these pathways not only reveals the molecular basis of renal fibrosis but also provides a vital blueprint for designing future targeted therapies.

Metabolic Reprogramming and Mitochondrial Dysfunction

Metabolic reprogramming is a hallmark of the fibrotic kidney, inextricably linked to signaling dysregulation. In conditions like DKD, MCs and TECs undergo a metabolic shift towards glycolysis, a phenomenon known as the Warburg effect.^27,51 This is often driven by mitochondrial dysfunction and results in lactic acid buildup, which stabilizes HIF-1α and promotes collagen production.²⁰ Mitochondrial dysfunction, characterized by impaired oxidative phosphorylation and fatty acid β-oxidation (FAO), precipitates energy failure in TECs.^20,52 The restoration of FAO via PPARα activation has been shown to ameliorate fibrosis.⁵² Aberrant lipid metabolism contributes to lipotoxicity and ferroptosis.⁵ The accumulation of lipid peroxides not only induces cell death but also releases pro-inflammatory mediators that sustain the fibrotic response. Nanomedicine strategies focusing on “metabolic correction”—such as delivering FAO-promoting genes or mitochondrial-targeted antioxidants—offer a novel therapeutic paradigm.^39,53

Epigenetic Regulation

The pathogenesis of renal fibrosis is orchestrated by the confluence of genetic susceptibility and epigenetic regulation. The latter involves dynamic, heritable phenotypic alterations independent of DNA sequence changes, playing a decisive role in dictating cellular fate—including fibroblast activation, TEC senescence, and transdifferentiation—thereby shaping the pro-fibrotic microenvironment. These epigenetic modifications serve as a mechanistic conduit, bridging transient pathological stimuli to persistent perturbations in gene expression.

Dysregulation of DNA methylation represents a hallmark of the fibrotic process. This is typically characterized by global genomic hypomethylation, which instigates genomic instability, concurrent with the aberrant hypermethylation of specific tumor suppressor and anti-fibrotic gene promoters. A quintessential example is the RASAL1 gene, which encodes a negative regulator of the Ras signaling pathway. Hypermethylation of the RASAL1 promoter results in its transcriptional silencing, leading to the constitutive activation of Ras signaling.⁵⁴ This effectively abrogates the inhibitory brake on fibroblast activation, significantly accelerating fibrogenesis. Such precise, targeted gene silencing underscores the specificity of DNA methylation in modulating fibrosis.

Histone modifications—including acetylation, methylation, and phosphorylation of histone tails—constitute an intricate “histone code” that governs chromatin accessibility and transcriptional competence. In renal fibrosis, the aberrant upregulation of histone deacetylases leads to histone hypoacetylation, fostering an epigenetic landscape that promotes the transcription of pro-fibrotic genes such as α-SMA and collagen. Conversely, the repressive mark H3K27me3, catalyzed by methyltransferases like EZH2, accumulates at the promoters of anti-fibrotic genes. This induces their long-term silencing, providing a structural epigenetic basis for the sustenance of the fibrotic niche.^50,55

Non-coding RNAs form a sophisticated post-transcriptional regulatory network, acting as “molecular fine-tuners”. MicroRNAs (miRNAs), such as the pro-fibrotic miR-21 and miR-192, potentiate the PI3K/Akt and TGF-β pathways by suppressing protective targets such as phosphatase and tensin homolog (PTEN) and Smad7.^19,29 In contrast, the anti-fibrotic miR-29 family directly targets multiple collagen mRNAs, and its downregulation is a pivotal event driving excessive ECM deposition. Furthermore, long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) function as competitive endogenous RNAs (ceRNAs); acting as “molecular sponges”, they sequester miRNAs to alleviate the repression of target genes. This mechanism critically regulates signaling nodes such as TGF-β/Smad and Wnt/β-catenin, thereby modulating the equilibrium between ECM synthesis and degradation.⁵⁶

In summary, the tripartite epigenetic machinery of DNA methylation, histone modifications, and non-coding RNAs intertwines to transduce external pathological stimuli—such as hyperglycemia, angiotensin II, and TGF-β1—into stable, persistent phenotypic alterations. This establishes the “molecular memory” of renal fibrosis, offering a profound explanation for the refractory nature of the disease and its clinical irreversibility. Crucially, it identifies novel molecular targets for the development of “epigenetic editing” therapies aimed at reversing established renal fibrosis. Collectively, these multidimensional mechanisms—spanning multicellular interactions, signaling networks, metabolic shifts, and epigenetic modulation—constitute the integrated pathogenic landscape of renal fibrosis, as comprehensively illustrated in Figure 1. In order to clarify the relationship between the mechanisms of renal fibrosis, Table 1 below is presented.

Table 1.

Mechanisms of Renal Fibrosis Across Multiple Biological Layers

Mechanism Classification	Key Components	Function/Role	Core Molecular Pathways	Characteristics
Cellular Level
1.1 Myofibroblasts (MYFs)	—	Synthesize and deposit aberrant ECM; Exert contractile forces	TGF-β/Smad, Wnt/β-catenin, Notch	Core effector cells marked by α-SMA expression. Diverse origins: Resident fibroblasts, pericytes, MMT, and EndoMT. Heterogeneity: Distinct subpopulations for synthesis vs contraction.
1.2 Resident Renal Cells	Renal tubular epithelial cells (TECs)	Secrete pro-fibrotic factors; Undergo partial EMT; Amplify inflammation via cell death	TGF-β/Smad, Wnt/β-catenin, NOX4 axis, Ferroptosis (GPX4/System Xc-)	G2/M arrest drives the senescence-associated secretory phenotype. Ferroptosis: Lipid peroxidation and GPX4 inactivation create a pro-inflammatory loop. Pyroptosis: Releases IL-1β/IL-18 to recruit neutrophils.
	Mesangial cells	Mesangial matrix expansion; Glomerulosclerosis induction	TGF-β/CTGF, Wnt/β-catenin, HIF-1α	Metabolic shift: High glucose drives a switch to glycolysis (Warburg effect). Regulation: GABP transcription factor binds the GLI1 promoter to sustain activation.
	Vascular endothelial cells and pericytes	Endothelial injury leads to microvascular rarefaction; hypoxia can induce pericyte transdifferentiation.	TGF-β, hypoxia	A vicious cycle of “hypoxia-tubular injury-fibrosis” mutually exacerbates pathology.
1.3 Immune Cells	Macrophages	M1: Release pro-inflammatory cytokines; M2: Secrete pro-fibrotic factors (TGF-β, Gal-3)	TGF-β/Smad, MAPK, mTORC1	Polarization imbalance: Skewed M1/M2 ratio drives progression. MMT: TSC1 loss promotes transition to α-SMA⁺ phenotypes via mTORC1.
	Neutrophils & CD8⁺ T cells	Neutrophils: Release NETs to activate macrophages; CD8⁺ T cells: Drive tubular EMT via GZMB	TLR2/4, CXCL	Biomarkers: Elevated serum CitH3 and dsDNA correlate with eGFR decline. Crosstalk: NETs bridge innate and adaptive immunity.
	Th17 Cells & Fibrocytes	Th17:Activate MYFs via IL-17A; Fibrocytes: Paracrine activation and matrix production	IL-17A/TGF-β, CD40-CD40L	Th17/Treg imbalance: Exacerbates renal injury. Fibrocytes: Bone marrow-derived hybrid phenotype (CD34⁺/Col1⁺).
2.Microenvironment	ECM proteomics	Provide mechanical scaffold; Drive mechanotransduction signaling	Integrin signaling, TG2/LOXL2 activity	Composition: Accumulation of collagen I/III/IV and fibronectin. Stiffening: Cross-linking enzymes create a physical barrier to drug penetration.
	Oxidative stress and Niche	Scavenge ROS (impaired); Activate fibroblasts via ROS signaling	NOX4/PKCα/MAPK, Nrf2, HIF-1α	GPX3 deficiency: Triggers self-amplifying oxidative cycles. Fibrotic niche: A “core-periphery” pattern comprising hypoxic, stiff, and oxidative zones.
	Fibrotic niche	A dynamic pathological microenvironment composed of multiple cells and abnormal ECM	PKCα/MAPK/STAT3, TGF-β, HIF-1α	Single-cell spatial transcriptomics reveals a “core–periphery” differentiation pattern within fibrotic foci.
3.Epigenetic Regulation	DNA methylation	Silence anti-fibrotic genes; Induce genomic instability	Ras signaling	Molecular memory: Hypermethylation of RASAL1 promoter perpetuates fibroblast activation. Global hypomethylation vs promoter-specific hypermethylation.
	Histone modification	Regulate chromatin accessibility; Promote pro-fibrotic gene transcription	TGF-β/Smad	Histone code: HDAC upregulation causes hypoacetylation. H3K27me3: Repressive mark silencing anti-fibrotic genes (via EZH2).
	Non-coding RNAs	Act as “molecular fine-tuners”; Modulate signaling nodes	TGF-β/Smad, PI3K/Akt	miRNA: miR-21 (pro-fibrotic) vs miR-29 (anti-fibrotic). ceRNA network: lncRNAs/circRNAs sponge miRNAs to de-repress targets.

Therapeutic Strategies for Renal Fibrosis: From Fundamental Interventions to Cutting-Edge Exploration

Building upon the intricate molecular landscape of renal fibrosis, therapeutic paradigms are evolving from single-pathway inhibition to systemic interventions targeting complex disease networks. Current clinical translation efforts face multifaceted challenges, prompting emerging breakthroughs to focus on three strategic frontiers: optimizing targeting specificity, which aims to enhance drug accumulation within fibrotic lesions via spatiotemporally controlled delivery systems, thereby minimizing systemic toxicity,²² establishing synergistic multi-target therapies, leveraging combination regimens or the multi-component regulatory properties of Traditional Chinese Medicine to counteract the compensatory signaling activation often seen with monotherapies;⁵⁷ and reshaping the fibrotic microenvironment, designed to disrupt the vicious cycle of hypoxia, oxidative stress, and matrix stiffening.¹⁹ This section systematically examines these strategies, spanning from foundational risk management to vanguard regenerative medicine.

Foundational Pillars and Their Limits—Etiological Control, Metabolic Correction, and Residual Risk

Effective management of renal fibrosis is predicated on the rigorous mitigation of upstream etiologies and modifiable risk factors. The current clinical cornerstone rests on lifestyle interventions, such as salt restriction and weight optimization, and pharmacological blockade. RASI serve as first-line therapy, conferring renoprotection by abrogating AngII-dependent pro-fibrotic signaling and lowering intraglomerular pressure. The advent of SGLT2 inhibitors marks a paradigm shift; their benefits extend beyond glucose lowering, driven by a multifaceted mechanism spanning the restoration of tubuloglomerular feedback, amelioration of hypoxia, and suppression of inflammation.⁷ Crucially, recent evidence suggests SGLT2 inhibitors correct tubular metabolic reprogramming, primarily by reinvigorating FAO, thereby counteracting hyperglycemia-induced structural remodeling—characterized by glomerular basement membrane thickening, podocyte depletion, and mesangial expansion—which ultimately precipitates tubulointerstitial fibrosis⁸ (Figure 4). Concurrently, managing hyperlipidemia is essential, as lipotoxicity acts as another potent driver of fibrogenesis.⁵

Figure 4.

Structural alterations in diabetic kidney disease (DKD) driving renal fibrosis. This schematic depicts the progression from normal glomerular architecture to the pathological hallmarks of DKD, including glomerular basement membrane (GBM) thickening, podocyte loss, mesangial expansion with collagen deposition, and tubulointerstitial fibrosis. Hyperglycemia-induced upregulation of sodium-glucose cotransporters (SGLT1/2) exacerbates glomerular and tubular injury, thereby fueling the fibrotic cascade. Reproduced from Vartak et al, 2021⁸ with permission from Advanced Drug Delivery Reviews. Symbol legend: Red arrows indicate the directional flow of blood and urine, as well as the transcellular pathway of glucose reabsorption; black arrows serve as leader lines for structural annotations and pathological processes; purple dots represent glucose molecules; dark grey fibrous structures within the diseased glomerulus denote collagen deposition, and multi-colored circular icons (top right) represent infiltrating leukocytes.

However, despite these standard-of-care agents constituting a robust defensive baseline, a formidable “therapeutic ceiling” persists. This limitation stems from a fundamental pathological reality: these therapies primarily address upstream drivers (hemodynamics and metabolism). Once fibrosis surpasses a point of no return, the dense, cross-linked ECM barrier and the epigenetically fixed myofibroblast phenotype constitute a significant “residual risk” that upstream inhibition fails to resolve. Consequently, the inability to reverse established scarring creates a critical bottleneck, underscoring the urgent imperative for precision nanomedicine strategies capable of directly targeting and reshaping the fibrotic niche.

Targeting Inflammation and Signaling Pathways—Current Clinical Landscape

In the management of mid-to-late stage CKD, particularly where proteinuria or functional decline persists despite maximal RASI therapy, targeting the inflammatory and signaling cascades that drive downstream fibrosis has become a paramount strategy.

A significant paradigm shift involves the mineralocorticoid receptor antagonists (MRAs). Finerenone, a novel non-steroidal MRA, distinguishes itself from traditional agents like spironolactone by selectively inhibiting mineralocorticoid receptor overactivation—a potent driver of inflammation and fibrosis—with a markedly reduced risk of hyperkalemia.⁹ Landmark trials, notably FIDELIO-DKD, have unequivocally demonstrated its efficacy in reducing renal composite endpoints in type 2 diabetes. However, it is crucial to recognize that its efficacy is primarily preventative regarding fibrosis progression, rather than curative for established scars. This distinction underscores the persistent challenge of reversing aberrant ECM deposition, which remains largely unresponsive to upstream receptor blockade once the fibrotic architecture is solidified.

Endothelin receptor antagonists constitute another vital therapeutic class. Sparsentan, a first-in-class dual endothelin and angiotensin II receptor antagonist, has recently garnered approval for IgA nephropathy and focal segmental glomerulosclerosis (FSGS).¹⁰ By simultaneously blocking vasoconstrictive and pro-fibrotic endothelin-1 pathways, it significantly delays glomerulosclerosis. Nevertheless, its clinical utility is constrained by class-specific adverse effects, primarily fluid retention and potential hepatotoxicity, necessitating rigorous monitoring programs which limit widespread adoption.

Immunomodulatory strategies remain indispensable for immune-mediated nephropathies. While systemic glucocorticoids effectively suppress primary inflammation, their long-term utility is compromised by severe off-target toxicity. Targeted-release formulations, such as enteric-coated budesonide, represent an early evolution towards precision therapy.¹¹ By releasing the drug specifically in the distal ileum to target Peyer’s patches, this formulation mitigates pathogenic IgA production while reducing systemic exposure.

Collectively, while these pharmacological agents exemplify the vanguard of current clinical practice, they are fundamentally limited by the trade-off between systemic toxicity and local efficacy.²² Furthermore, none of these agents possess the intrinsic capability to dismantle the dense, cross-linked ECM of advanced fibrosis, highlighting the urgent imperative for nanomedicine strategies capable of deep lesion penetration and microenvironmental reprogramming.

Emerging Targeted Therapies and Biologics—Novel Strategies and Their Limitations

With a deepening grasp of the molecular mechanisms driving renal fibrosis, a diverse array of targeted therapies and biologics has entered the research landscape. These strategies primarily categorize into macromolecular biologics and small-molecule inhibitors.

Biologics targeting key fibrotic mediators, particularly the TGF-β axis, initially showed promise. Approaches utilizing monoclonal antibodies to neutralize TGF-β isoforms, exemplified by fresolimumab, demonstrated efficacy in preclinical models.⁶ However, their clinical translation has been stymied by inconsistent efficacy and safety concerns. This failure is likely attributable to two distinct hurdles. Biologically, the pleiotropic nature of TGF-β means that systemic neutralization disrupts immune homeostasis. Physically, and perhaps more critically, the macromolecular nature of these biologics hinders their penetration into the cross-linked, stiffened ECM of fibrotic lesions. This dense physical barrier restricts perfusion, preventing antibody-drug candidates from reaching therapeutic concentrations at cellular target sites within the fibrotic core.

Small-molecule inhibitors, conversely, possess superior tissue permeability but struggle with specificity. Pirfenidone, approved for idiopathic pulmonary fibrosis (IPF), functions via multiple mechanisms, including inhibiting TGF-β synthesis and exerting anti-inflammatory effects.²² While Phase II trials in DKD and FSGS suggested potential in delaying eGFR decline, its widespread renal application is hampered by dose-limiting adverse events, manifesting primarily as gastrointestinal and skin toxicity, resulting from widespread systemic distribution. Similarly, inhibitors targeting the Wnt/β-catenin pathway or cellular senescence remain in exploratory stages, with off-target effects posing significant safety risks.

Distinct from the broad-spectrum immunosuppression of glucocorticoids or the pleiotropic effects of MRAs (discussed in Targeting Inflammation and Signaling Pathways—Current Clinical Landscape), emerging strategies aim to surgically ablate specific pro-inflammatory nodes. Monoclonal antibodies targeting IL-1β, such as canakinumab, have demonstrated potential in reducing cardiovascular and renal events in secondary analyses of the CANTOS trial. Similarly, NLRP3 inflammasome inhibitors are being developed to arrest the sterile inflammation characteristic of fibrosis.⁶ However, these precision biologics face the same “delivery paradox” as anti-TGF-β agents: while they theoretically minimize off-target toxicity compared to steroids, their large molecular size hinders effective penetration into the fibrotic kidney, often necessitating high systemic doses that re-introduce safety concerns.

Collectively, current targeted therapies face a dichotomous dilemma: small molecules suffer from systemic toxicity due to poor selectivity, while highly specific biologics are impeded by the physical barrier of the fibrotic microenvironment.²² This “delivery bottleneck” underscores the urgent imperative for nanomedicine strategies capable of both deep lesion penetration and cell-specific targeting.

Tissue Repair and Regeneration—Cells, Genes and Novel Therapeutic Platforms

Current vanguard research in renal fibrosis pivots towards regenerative medicine and gene intervention strategies, aiming not merely to arrest progression but to actively suppress advanced fibrosis and orchestrate the regeneration of renal architecture and function. While predominantly residing in preclinical or early clinical phases, these approaches represent a fundamental paradigm shift in the therapeutic landscape.

Within the realm of stem cell therapies, mesenchymal stem cells (MSCs) have been the subject of extensive investigation.⁵⁸ MSCs predominantly exert their salutary effects via paracrine mechanisms—secreting anti-inflammatory cytokines, pro-angiogenic factors, and extracellular vesicles (EVs)—to modulate immune responses and foster tissue repair.⁵⁹ However, despite robust efficacy in animal models, large-scale clinical translation remains stalled. Major translational hurdles include the rapid clearance of transplanted cells and low survival rates in the harsh, hypoxic, and inflammatory fibrotic microenvironment. This necessitates advanced delivery vectors—such as cytocompatible nanoscaffolds or hydrogels—to enhance retention and viability, thereby prolonging the therapeutic window.

To circumvent the safety concerns associated with live cell transplantation, such as potential tumorigenicity and immunogenicity, EVs—with a specific focus on exosomes—derived from stem cells have emerged as a promising “cell-free” therapeutic paradigm.⁵⁹ These nanoscale carriers transport a diverse cargo of bioactive molecules ranging from miRNAs to functional proteins, thereby recapitulating the regenerative potency of their parental cells. Current efforts are concentrated on establishing standardised isolation protocols and engineering targeted delivery systems to enhance their renal tropism.

Gene therapy offers precision at the molecular root. Strategies include viral vectors for overexpression of protective genes, such as Klotho, CRISPR-Cas9 editing for stable genetic modification, and RNA interference (RNAi) to silence pro-fibrotic targets, a strategy exemplified by miR-21 inhibitors currently in Phase II trials.²⁹ However, the clinical utility of these potent tools is strictly limited by the delivery vehicle: viral vectors suffer from immunogenicity, while naked nucleic acids are rapidly degraded. This underscores the critical need for non-viral nanocarriers, most notably lipid nanoparticles (LNPs), to ensure intracellular delivery and evasion of endosomal entrapment.^16,22

In summary, while regenerative and genetic strategies hold the promise of reversal, they are functionally constrained by “delivery bottlenecks”—poor retention, low stability, and off-target distribution. Consequently, the ability to deliver these sophisticated therapeutics precisely to the lesion core while sparing healthy tissue is critical. In this context, nanomedicine offers a transformative solution. By exploiting size-dependent effects and versatile design, intelligent nanocarriers enable the targeted delivery and sustained release of chemical, genetic, and cellular therapies, positioning nanomedicine as the key enabler for the future of renal fibrosis treatment.²³

Applications of Nanomedicine in the Treatment of Renal Fibrosis

Nanomedicine offers a dual-modality approach for treating renal fibrosis, underpinned by its precisely controllable physicochemical characteristics. Primarily, nanocarriers serve as smart drug delivery platforms. By employing surface functionalization, these systems achieve specific recognition of renal lesions and effector cells, facilitating the efficient transport of various anti-fibrotic agents. This capability significantly enhances local drug concentration and therapeutic efficacy while effectively mitigating systemic toxicity. Concurrently, certain nanomaterials possess intrinsic therapeutic bioactivity: specific nanoparticles function as antioxidant nanozymes to scavenge free radicals, regulate the immune microenvironment to suppress inflammation, or directly interfere with pro-fibrotic pathways, thereby inhibiting collagen overproduction and scarring at the source.

Based on the in-depth analysis of the multicellular network and key signaling pathways provided earlier, nanoparticle design is evolving from “passive delivery” to “mechanism-guided precision intervention”. The following sections will detail, according to nanoparticle classification, how these molecular insights are integrated into the engineering of targeting ligands, responsive release mechanisms, and synergistic strategies to build future-oriented intelligent therapeutic systems.

Inorganic Nanoparticles

Inorganic nanoparticles are prized for their tunable size, distinct optical properties, and, crucially, their intrinsic enzyme-mimetic activities. Unlike organic carriers that serve primarily as vehicles, inorganic systems often function as “active participants” in therapy (Table 2).

Table 2.

Representative Inorganic Nanomaterials for Renal Fibrosis: Material Design Decisions and Highlighted Results

Design Decision	Representative Platform	Target/Barrier Addressed	Key Result or Mechanistic Highlight	Ref.
Ultrasmall filtration plus receptor uptake	Folate-modified AuNPs	Injured TEC uptake after glomerular filtration	≤7 nm particles increased renal accumulation and inhibited p38α MAPK-driven fibrosis	[60]
Stimuli-responsive metal release	GSH-modified fluorescent AuNPs carrying Co2⁺	Acidic lysosomal fibrotic niche	pH-triggered release activated HIF-1α/miR-29c signaling with kidney-specific antifibrotic activity	[61,62]
Biodegradable ion reservoir	Mg(OH)2 or MgH2 nanoparticles	Acidic microenvironment and lipotoxic fibrosis	Buffered local acidity or delivered sustained H2 while suppressing Akt/mTOR and TGF-β/Smad signaling	[63,64]
Catalytic nanozyme design	CeO2 nanoclusters/NPs	Oxidative stress and metabolic reprogramming	Ce3⁺/Ce4⁺ cycling scavenged ROS, restored mitochondrial metabolism, and reduced EMT/fibrosis	[65–69]
Trace-element antioxidant reservoir	SeNPs and Se@SiO2	Post-AKI inflammation and ferroptosis-linked oxidative injury	Enhanced GPx activity and suppressed NLRP3/caspase-1 inflammation to limit fibrotic transition	[70–73]
Oxygen-carrying microenvironment modulation	Perfluorocarbon nanoparticles	Chronic hypoxia and inflammatory amplification	Improved renal oxygenation and reduced macrophage infiltration after ischemic injury	[74]

Metals

Gold Nanoparticles (AuNPs)

AuNPs have emerged as a dominant platform due to their facile surface chemistry and size-dependent renal kinetics. Current research has expanded into a diverse array of engineering paradigms, ranging from ligand-directed targeting, synergistic co-delivery, and stimuli-responsive actuation to green synthesis and device-drug integration.

To circumvent the inefficiency of passive accumulation, surface functionalization with specific ligands has been extensively engineered. A prime example involves folate-functionalized AuNPs with a diameter of 7 nm or less, designed to exploit the overexpression of folate receptors on injured TECs. This design represents a triple-action modality: the ultra-small size ensures glomerular filtration, the folate ligand facilitates cellular internalization, and the gold core intrinsically inhibits p38α MAPK phosphorylation to arrest fibroblast activation.⁶⁰ Comparatively, this active targeting strategy achieved a renal accumulation of 3.6% ID/g—significantly outperforming non-targeted counterparts and demonstrating superior efficacy in reducing collagen deposition in unilateral ureteral obstruction (UUO) models.

Beyond monotherapy, AuNPs serve as versatile scaffolds for combination regimens targeting distinct pathological axes. Addressing both metabolic and inflammatory drivers, a hybrid system co-delivering the SGLT2 inhibitor dapagliflozin with AuNPs was developed. This approach yielded a synergistic effect: the Au core provided structural stability and anti-inflammatory baselines, while dapagliflozin suppressed miR-192/miR-21 and enhanced autophagy.⁷⁵ This dual-targeting strategy highlights the potential of nanomedicine to overcome the limitations of single-drug therapies in complex metabolic diseases like DKD.

To achieve spatiotemporal precision, intelligent systems responsive to the fibrotic microenvironment have been created. Exploiting the acidic lysosomal pH of fibrotic tissues, glutathione-modified fluorescent AuNPs were engineered to trigger the release of therapeutic Co²⁺ specifically within the lesion.⁶¹ This “lock-and-key” release mechanism minimizes off-target toxicity in healthy tissues, addressing a major safety concern of metal-based therapeutics.

To address stability and oral delivery challenges, green synthesis protocols utilizing polyphenol-rich pomegranate peel extract have been established. This biomimetic formulation stabilizes the AuNPs while protecting bioactive polyphenols from gastrointestinal degradation. Mechanistically, these biogenic nanoparticles were shown to reverse oxidative stress by scavenging ROS and inhibiting protein glycosylation, while concurrently dampening inflammation through the MAPK/NF-κB/STAT3 axis. Consequently, this approach effectively preserved renal function in DKD models.⁷⁶

Expanding beyond systemic administration, AuNPs have been engineered into artificial kidney interfaces to enable device-drug synergistic therapy. In this innovative design, light excitation triggers the release of radical scavengers from the AuNP-modified surface during dialysis, while surface electronegativity prevents platelet adhesion. Notably, the reinfusion of treated dialysate was found to suppress FN1 expression. In CKD mice, this bioactive device significantly improved toxin clearance and anticoagulation while inhibiting systemic fibrosis, offering a novel paradigm for extracorporeal CKD management.⁷⁷

Collectively, AuNPs represent a versatile paradigm in renal fibrosis management, distinguishing themselves through the integration of targeted delivery, intrinsic signaling modulation, and device synergy. The evolution from passive accumulation to active, ligand-directed, and stimuli-responsive strategies has significantly amplified their therapeutic index. However, the translational horizon is currently clouded by the “retention-toxicity” trade-off. While the gold core offers stability, its non-biodegradability poses risks of long-term accumulation. Consequently, future engineering must pivot towards biodegradable hybrid architectures, exemplified by ultrasmall Au clusters assembled in degradable matrices, to reconcile the need for prolonged therapeutic action with the imperative of efficient renal clearance.

Silver Nanoparticles (AgNPs)

While primarily recognized for their broad-spectrum antimicrobial properties, AgNPs are gaining traction in renal protection strategies. Unlike AuNPs which function primarily through size-dependent kinetics, AgNPs exert therapeutic effects through the release of bioactive ions and surface interactions, necessitating precise control over their physicochemical stability.

To mitigate the inherent cytotoxicity of chemically synthesized silver, “green synthesis” approaches utilizing plant extracts have become a pivotal engineering paradigm. Conventional chemical reduction often involves toxic reagents including borohydride, leaving residues that exacerbate renal oxidative stress. In contrast, biosynthetic strategies employ antioxidant-rich plant extracts as dual reducing and capping agents. A prime example is the synthesis of AgNPs utilizing Helianthemum lippii extract, where the phytochemical corona shields renal cells from direct silver ion toxicity. Mechanistically, this formulation demonstrated superior efficacy in antagonizing cadmium-induced nephrotoxicity by restoring endogenous antioxidant defenses including SOD, CAT, and GSH, and suppressing pro-inflammatory cytokines such as TNF-α and IL-1β more effectively than the extract alone.⁷⁸ This underscores a “synergistic protection” model where the nanostructure enhances the bioavailability of the herbal extract while the extract mitigates the metal’s toxicity. Beyond inflammation, AgNPs exert therapeutic effects by dismantling the pathological vascular network. Unlike other noble metal nanoparticles, AgNPs possess a unique ability to normalize aberrant microvasculature by inhibiting the VEGF signaling pathway. This property is critical for blocking the pathological angiogenesis that often fuels the progression of renal fibrosis, positioning AgNPs as a dual-modulator of both the immune and vascular microenvironments.

The clinical application of AgNPs faces a steeper regulatory hurdle compared to AuNPs due to their narrow therapeutic index. A fundamental contradiction persists between ion release, which is required for therapy, and ion toxicity that causes mitochondrial damage and argyria. While the Helianthemum lippii study demonstrates that green synthesis can widen this window, it does not eliminate the risk of long-term heavy metal retention in the renal cortex. Therefore, future translational efforts must focus on establishing rigorous dose-response thresholds and developing renal-clearable ultrasmall Ag nanoclusters to ensure that therapeutic benefits are not outweighed by systemic nephrotoxicity.

Magnesium-Based Nanomaterials

Unlike noble metal nanoparticles (Au, Ag) which face the dilemma of long-term retention, magnesium-based nanomaterials offer a distinct advantage: they are inherently biodegradable and degrade into magnesium ions (Mg²⁺), an essential cofactor for enzymatic reactions. This property positions magnesium-based nanomaterials as ideal candidates for resolving the “clearance-retention paradox”.

To overcome the acidic microenvironment often induced by the degradation of synthetic polymers, magnesium hydroxide (Mg(OH)₂) nanoparticles have been engineered as pH-neutralizing agents within regenerative scaffolds. In renal tissue engineering, the rapid hydrolysis of poly(lactic-co-glycolic acid) (PLGA) typically creates an acidic niche that denatures ECM proteins and hinders regeneration. By integrating Mg(OH)₂ NPs, the scaffold achieves a “buffering effect”, neutralizing acidity and enhancing the preservation of bioactive fibroblast-derived ECM. Mechanistically, this composite scaffold significantly downregulated inflammation cytokines IL-1β and TNF-α and fibrosis markers α-SMA while upregulating regeneration-associated genes including Pax2 and Wt1. Comparatively, this strategy yielded a higher number of regenerated glomeruli than pristine scaffolds, demonstrating that modulating the chemical microenvironment is as critical as physical support for renal repair.⁶³

Addressing the limitations of hydrogen gas including low solubility and rapid diffusion, magnesium hydride (MgH₂) nanoparticles have been developed as a “solid-state hydrogen source” to combat metabolic-associated fibrosis. Dyslipidemia is a potent driver of CKD progression, yet targeting lipid-induced oxidative stress remains challenging. MgH₂ nanoparticles react with water in the digestive tract to provide a sustained, high-capacity release of H₂. In high-fat diet-induced CKD models, this strategy effectively mitigated renal interstitial fibrosis. Molecular analysis revealed that MgH₂ functions by restoring PTEN expression, which subsequently inhibits the Akt/mTOR and TGF-β/Smad2/3 signaling axes. This formulation overcomes the pharmacokinetic instability of traditional hydrogen water, offering a stable and controllable modality to disrupt the lipotoxicity-fibrosis link.⁶⁴

While the biodegradability of magnesium is a major asset, it presents a unique “double-edged sword” in the context of renal failure. The kidney is the primary route for magnesium excretion, and advanced CKD patients are prone to hypermagnesemia. Therefore, the degradation rate of Mg-based nanomaterials must be precisely tailored to match the reduced GFR of the patient. Rapid, uncontrolled release of Mg²⁺ could precipitate systemic toxicity, counteracting the local antifibrotic benefits. Future clinical translation requires smart coatings that couple degradation rates with real-time renal function monitoring.

Metal Oxides

Cerium Oxide Nanoparticles (CeO₂ NPs)

Distinguished by their reversible valence state switching (Ce³⁺/Ce⁴⁺), CeO₂ NPs function as regenerative anti-oxidants, mimicking the catalytic activities of SOD and CAT. Unlike organic scavengers which are stoichiometrically consumed, CeO₂ NPs operate as “everlasting” nanozymes. Current engineering strategies have evolved from simple antioxidation to targeting metabolic reprogramming and optimizing the “efficacy-safety” balance through precise size control.

Beyond scavenging ROS, recent evidence suggests CeO₂ NPs exert therapeutic effects by correcting the metabolic “Warburg effect” in fibrotic kidneys. Renal fibrosis is characterized by a shift from oxidative phosphorylation to aerobic glycolysis. PEGylated CeO₂ NPs were found to reverse this maladaptive reprogramming. Mechanistically, they inhibit hexokinase 2 expression and restore mitochondrial membrane potential, thereby shifting the metabolic flux back to oxidative phosphorylation. This metabolic correction effectively inhibited TGF-β1-induced EMT, restoring E-cadherin levels while reducing vimentin expression.⁶⁵

To enhance renal accumulation, delivery strategies have progressed from exploiting pathological permeability to ligand-mediated active targeting. Earlier findings indicated that approximately 10 nm CeO₂ NPs could passively accumulate in diseased kidneys—relying on increased vascular permeability—to abrogate fibrosis by inhibiting the TGF-β signaling pathway.⁶⁶ To further improve specificity, active targeting strategies have been introduced. For instance, lactoferrin-decorated CeO₂ NPs were engineered to target the overexpression of lactoferrin receptors on renal tissue. Compared to unmodified particles, this ligand-directed system achieved superior active delivery in UUO models, demonstrating enhanced anti-fibrotic effects via inhibition of the TGF-β1/Smad3 axis and activation of the Nrf2 pathway.⁶⁷

A critical divergence in engineering philosophy exists regarding the optimal particle size: “Ultra-small” for safety versus “Larger” for sustained prophylaxis. On one hand, to minimize systemic toxicity, ultra-small ceria nanoclusters (NCs, ≈1.2 nm) modified with hydrophilic ligands including succinic acid, PEG600, and PEG2000 have been developed. These sub-renal threshold clusters exhibit a high Ce³⁺/Ce⁴⁺ ratio for enhanced ROS scavenging and, crucially, demonstrate a smooth blood concentration curve with rapid renal clearance and reduced organ accumulation. In CKD mice, these renal-clearable NCs effectively suppressed oxidative stress, inflammation, and fibrosis, highlighting their potential as safe clinical redox nanomedicines.⁶⁸ On the other hand, for prophylactic applications where long-term protection is required, larger particles may be advantageous. A comparative study of three sizes (46, 81, 118 nm) revealed that 118 nm CeO₂ NPs possessed superior renal retention, with approximately 25% persisting in the kidneys 21 days after ischemia-reperfusion injury (IRI). This sustained retention allowed for effective prophylaxis (Figure 5), significantly improving renal function markers and inhibiting fibrosis through Nrf2-mediated oxidative stress reduction and the suppression of M1 macrophage polarization.⁶⁹

Figure 5.

Schematic illustration of CeO₂ NPs in renal ischemia-reperfusion injury (IRI) and renal fibrosis. This schematic illustrates the protective pathways mediated by CeO₂ NPs, primarily through scavenging reactive oxygen species (ROS) and attenuating the inflammatory response, thereby alleviating acute kidney injury and inhibiting the progression to chronic renal fibrosis. Reproduced from Zhou et al, 2022⁶⁹ with permission from Biomaterials. (Note: The abbreviation “CONPs” appearing in the original figure corresponds to “CeO₂ NPs” used in this manuscript). Symbol legend: Thick blue arrows indicate the experimental workflow and schematic transitions; thin black arrows indicate the polarization of M0 macrophages to the M1 phenotype; red crosses (✕) placed over black arrows represent the blockade or inhibition of this macrophage polarization, whereas crosses next to text denote ineffective biological outcomes; blue check marks (✓) represent effective therapeutic outcomes; thin blue downward (↓) and red upward (↑) arrows denote a decrease or increase, respectively, in the levels of intracellular ROS and pro-inflammatory cytokines; curved light-blue arrows (bottom right) illustrate the renal accumulation and cellular uptake of the nanoparticles.

The conflicting evidence regarding optimal size highlights a fundamental principle: Structure follows function. Ultra-small nanoclusters represent the ideal “therapeutic” model for established CKD, prioritizing biosafety and clearance to allow for repeated dosing. Conversely, larger nanoparticles serve as a “prophylactic depot”, ideal for high-risk surgical scenarios where a single administration needs to provide lasting protection. Future translation must strictly categorize CeO₂ NPs based on these distinct clinical scenarios.

Zinc Oxide Nanoparticles (ZnO NPs)

Unlike noble metals or stable oxides, ZnO NPs offer a unique “trace element supplementation” strategy. Zinc is an essential cofactor for over 300 enzymes, including key antioxidants. Consequently, ZnO NPs function not only as ROS scavengers but also as biological modulators that restore zinc homeostasis in diseased kidneys. Their therapeutic efficacy is underscored by a multi-target defense network involving the regulation of oxidative stress, inflammation, and programmed cell death.

In the context of DKD, ZnO NPs have demonstrated remarkable efficacy in preserving the filtration barrier. Chronic hyperglycemia often leads to podocyte injury and basement membrane thickening. Administration of ZnO NPs in STZ-induced models significantly reversed these pathologies. Mechanistically, they block the TGF-β1/Smad3 fibrotic axis, reducing the deposition of FN1 and collagen IV. Crucially, recent findings reveal a novel mechanism where ZnO NPs inhibit podocyte necroptosis and pyroptosis by targeting the Ripk1/Ripk3/Mlkl pathway.⁷⁹ This intervention not only reduced oxidative stress markers but also restored the expression of nephrin and podocin, thereby preventing albuminuria.⁸⁰

Beyond metabolic diseases, ZnO NPs exert potent protective effects against chemical-induced renal toxicity. In thioacetamide-induced injury models, ZnO NPs functioned as a “redox restorer”. Treatment significantly suppressed lipid peroxidation indicated by MDA while replenishing depleted antioxidant reserves, including GSH, SOD, and CAT. This restoration of redox balance translated into marked structural protection, inhibiting α-SMA expression and ameliorating hepatic-renal crosstalk toxicity.⁸¹

Recognizing that monotherapy often hits a therapeutic ceiling, combination strategies pairing ZnO NPs with pharmacological agents have emerged as a superior paradigm. In acute IRI models, co-treatment with ZnO NPs and milrinone yielded a synergistic protective effect. This combination outperformed either agent alone by simultaneously activating the Nrf2 antioxidant pathway and inhibiting NF-κB-mediated inflammation. Consequently, it drastically reduced vascular permeability and KIM-1 levels.⁸² Similarly, in UUO models, combining ZnO NPs with the angiotensin II receptor blocker losartan provided enhanced renoprotection. This dual-modal therapy targeted the TNF-α/IL-6 inflammatory axis and the BAX/BCL2 apoptotic pathway more effectively than losartan monotherapy, highlighting the potential of ZnO NPs as an adjuvant to standard-of-care RASI blockade.⁸³

While ZnO NPs offer pleiotropic benefits, their biosafety profile is intrinsically linked to solubility kinetics. Unlike insoluble gold or ceria, ZnO NPs dissolve in the acidic environment of lysosomes, releasing Zn²⁺ ions. While Zn²⁺ is essential, an intracellular “zinc overload” can trigger mitochondrial dysfunction and ROS generation—a phenomenon known as the “Janus effect”. Therefore, the clinical translation of ZnO NPs necessitates precise dosing regimens that stay within the physiological “Goldilocks zone”, ensuring that Zn²⁺ release supports enzymatic function without crossing the threshold into cytotoxicity.

Manganese Oxide Nanoparticles (Mn₃O₄ NPs)

Mitochondrial dysfunction stands as a central hub in CKD pathogenesis, inextricably linked to oxidative stress. A major limitation of conventional antioxidants is their “indiscriminate scavenging”, which often disrupts physiological redox signaling required for normal cell survival. Consequently, precision antioxidant strategies based on nanotechnology offer superior therapeutic potential by targeting the “mitochondria-oxidative stress axis”.

To achieve selective restoration of mitochondrial function, citrate-functionalized Mn₃O₄ NPs (C-Mn₃O₄ NPs) have been engineered as a targeted redox modulator. Unlike non-specific scavengers, these nanoparticles are designed to specifically accumulate within the mitochondria of TECs. Their primary mechanism involves mimicking the catalytic activities of SOD and catalase to selectively eliminate excess superoxide anions and hydrogen peroxide. Crucially, this approach lowers pathological ROS levels while preserving the physiological redox balance necessary for cellular signaling.⁸⁴ In cisplatin-induced CKD models characterized by severe mitochondrial distress, C-Mn₃O₄ NPs functioned as a “mitochondrial reconditioner”. By effectively interrupting the “oxidative stress-mitochondrial damage” loop, treatment significantly mitigated glomerulosclerosis and interstitial fibrosis after four weeks. Mechanistic validation confirmed that these benefits stemmed from the protection of mitochondrial structural integrity and the suppression of pro-inflammatory cytokines, outperforming the efficacy of standard antioxidant regimens. This strategy highlights the feasibility of treating multifaceted diseases like CKD through nanomedicine-mediated organelle repair.

While Mn-based nanozymes exhibit excellent mitochondrial targeting, their translation is shadowed by the risk of neurotoxicity. Free manganese ions released from nanoparticle degradation can cross the blood-brain barrier and accumulate in the basal ganglia, leading to Parkinson-like symptoms. Therefore, unlike iron or calcium-based materials, the long-term biodistribution and brain accumulation of Mn₃O₄ NPs must be rigorously evaluated. Future designs should focus on chelator-integrated clearance mechanisms or ensuring that the dosage required for renal protection is strictly below the threshold for neurological uptake.

Non-Metals

Silica Nanoparticles (SiO₂ NPs)

Non-metallic nanoparticles represent a promising frontier in renal fibrosis treatment, favored for their high stability and versatile surface chemistry. Specifically, mesoporous SiO₂ NPs possess a unique porous architecture that enables high drug loading (>500 mg/g) alongside pH-responsive degradation. Current research leverages these properties through two distinct strategies: mitigating the nephrotoxicity of systemic drugs and engineering bioactive composites for direct fibrosis intervention.

To decouple the therapeutic efficacy of chemotherapeutics from their inherent renal toxicity, SiO₂ NPs serve as “shielding” carriers. Methotrexate (MTX), a potent antifibrotic and anticancer agent, is clinically limited by its severe nephrotoxicity. By encapsulating MTX within nano-silica, the pharmacokinetics are altered to favor controlled release rather than toxic accumulation. In leukemia models, this MTX-loaded silica system markedly reduced α-SMA and collagen IV expression by suppressing the IL-6/NF-κB inflammatory axis and blocking TGF-β1/Smad3 signaling. Comparatively, this nano-formulation maintained the drug’s therapeutic potency while significantly alleviating the renal injury and fibrosis observed with free MTX administration, presenting a translatable strategy for safe chemotherapy.⁸⁵

Addressing the critical transition from acute kidney injury (AKI) to fibrosis, composite strategies utilizing silica as a scaffold for trace elements have been developed. Selenium (Se) is a potent antioxidant but lacks stability. To harness its potential, porous selenium-silica nanospheres (Se@SiO₂) were engineered. In this composite, the silica shell provides stability while the Se core acts as the redox active center. In IRI models, Se@SiO₂ prophylaxis significantly alleviated tubular damage and apoptosis. Mechanistically, it functions by reducing ROS, boosting endogenous glutathione levels, and suppressing inflammatory cascades, thereby effectively blocking the progression of post-AKI fibrosis and atrophy.⁷⁰

While SiO₂ NPs offer superior loading capacity compared to organic polymers, their clinical application in nephrology faces the challenge of degradation kinetics. Unlike PLGA which hydrolyzes rapidly, mesoporous silica degrades slowly into orthosilicic acid. In compromised kidneys characterized by low GFR, there is a risk that silica fragments could accumulate in renal tubules or glomeruli before full degradation, potentially inducing secondary inflammation akin to a silicosis-like reaction. Future engineering must focus on “ultrasmall” silica dots smaller than 10 nm or doping with biodegradable elements such as Ca and Mg to accelerate hydrolysis, ensuring that the carrier itself does not become a burden to the fibrotic kidney.

Selenium Nanoparticles (SeNPs)

Se, an essential trace element, is integral to the active center of glutathione peroxidase (GPx). However, traditional Se supplements face a narrow therapeutic window between efficacy and toxicity. SeNPs overcome this limitation by offering lower metabolic toxicity and high bioavailability. Acting as “nano-Se reservoirs”, they correct renal tissue Se deficiency while functioning as potent ROS scavengers and anti-inflammatory modulators to halt the transition from injury to fibrosis.

Addressing the Se deficiency often observed in AKI, a Se-rebalancing strategy has been engineered to arrest the fibrotic cascade. By utilizing bovine serum albumin (BSA)-stabilized SeNPs, engineers achieved targeted renal accumulation and efficient endocytosis by TECs. Mechanistically, this nanosystem functioned as a dual-modal inhibitor: it upregulated intracellular GPx-1 to scavenge ROS and simultaneously suppressed the NLRP3 inflammasome by blocking the caspase-1-mediated maturation of IL-1β/IL-18. Consequently, this intervention significantly mitigated tissue damage and inhibited post-AKI fibrosis, validating the concept of “trace element nanomedicine” for inflammatory renal disease.⁷¹

In the metabolic context of DKD, monotherapy often fails to control the complex interplay of hyperglycemia and oxidative stress. To address this, a combinatorial oral therapy pairing chitosan-stabilized SeNPs (Ch-SeNPs) with MET was developed. While metformin regulates glucose hemostasis, Ch-SeNPs provide a critical antioxidative shield. This synergistic duo significantly outperformed monotherapy by downregulating the polyol pathway enzyme aldose reductase and suppressing interstitial markers including vimentin, desmin and nestin. Furthermore, it inhibited the TGF-β1 fibrotic axis and pro-inflammatory cytokines such as TNF-α and IL-6, offering a comprehensive defense against microvascular diabetic complications.⁷²

Beyond metabolic and ischemic injuries, SeNPs demonstrate robust nephroprotective effects against environmental toxins. In models of sodium arsenite-induced nephrotoxicity, SeNPs served as a “bio-antidote”. Treatment reversed the toxic effects on TECs by inhibiting oxidative stress-mediated apoptosis and inflammation. This protection translated into preserved renal function and reduced histopathological fibrosis, confirming the biocompatibility and utility of SeNPs in mitigating pollutant-induced renal degeneration.⁷³

The transition of Se from a dietary supplement to a nanomedicine hinges on “valence engineering” and “targeting precision”. SeNPs (Se⁰) exhibit lower acute toxicity than selenite (Se⁴⁺) or selenate (Se⁶⁺). However, the long-term accumulation of elemental Se in renal tubules remains a potential concern. Future translational efforts must focus on kidney-targeting peptide modifications to enhance tubular selectivity and developing biodegradable composite matrices to ensure controlled release without systemic Se overload.

Carbon-Based and Functional Nanomaterials

This category, represented by graphene quantum dots (GQDs) and perfluorocarbon nanoparticles (PFPs), offers distinct therapeutic paradigms based on their dimensional and chemical properties. GQDs smaller than 10 nm leverage quantum confinement for subcellular targeting, while PFPs ranging from 100 to 200 nm exploit high gas solubility to modulate the hypoxic microenvironment.

To address mitochondrial dysfunction in proteinuric kidney diseases, GQDs have been engineered to stabilize podocyte bioenergetics. In Adriamycin-induced nephropathy, GQDs demonstrated a preferential accumulation in the glomerulus. Mechanistically, they exert protection by downregulating transient receptor potential channel 5 (TRPC5) activity. This blockade inhibits pathological calcium influx, thereby restoring mitochondrial membrane potential and enhancing cristae morphology. Consequently, this intervention mitigated cytoskeletal collapse and significantly reduced proteinuria and collagen I deposition.⁸⁶ Furthermore, in UUO models, GQDs function as broad-spectrum ROS scavengers. By intercepting the ROS/TGF-β1 feedback loop, they effectively inhibited Smad2/3 phosphorylation and the EMT. This dual action—protecting podocyte mitochondria and suppressing tubular oxidative stress—positions GQDs as a versatile tool for halting fibrosis progression.⁸⁷

Targeting the “chronic hypoxia hypothesis” of renal fibrosis, PFPs serve as superior oxygen carriers capable of holding approximately 18 times more oxygen than blood. In ischemia-reperfusion induced AKI, PFP administration rapidly ameliorated renal oxygenation, breaking the vicious cycle of “hypoxia-inflammation-fibrosis”. Metabolomic and molecular analyses revealed that PFPs promote repair by upregulating SLC22A19, a short-chain fatty acid transporter, and downregulating hyaluronic acid (HA) synthesis. This metabolic and microenvironmental reprogramming resulted in decreased NF-κB activation, reduced macrophage infiltration, and significant preservation of renal architecture.⁷⁴

While carbon-based materials show promise, they face scrutiny regarding “carbon nanotoxicology”. Non-degradable carbon accumulation can potentially induce granulomas or chronic inflammation. GQDs, due to their ultra-small size, favor renal clearance, but their long-term interaction with DNA requires careful assessment. Conversely, PFPs must overcome the risk of gas embolism and stability issues. Future engineering should focus on “hybrid systems” such as PFPs-GQDs to combine oxygenation with antioxidant therapy, while rigorously mapping the long-term metabolic fate of the carbon lattice.

Organic Nanoparticles

Lipid Nanoparticles (LNPs)

LNPs constitute the most clinically advanced class of nanomedicines, favored for their phospholipid-based biocompatibility and structural versatility. By mimicking endogenous transport vesicles, they can be broadly categorized into biomimetic lipoproteins utilizing natural lipid-protein pathways and engineered liposomes consisting of synthetic phospholipid vesicles. These platforms excel in enhancing the bioavailability of hydrophobic drugs, enabling epigenetic modulation, and protecting fragile nucleic acid payloads. Together with chitosan-, polyester-, and dendrimer-based systems, these organic carriers illustrate how renal nanomedicine shifts from simple encapsulation toward coordinated control of cargo stability, epithelial uptake, stimulus-responsive release, and barrier penetration (Table 3).

Table 3.

Organic and Polymeric Nanocarriers for Renal Fibrosis: Targeting, Release, and Barrier-Crossing Design Decisions

Design Decision	Representative Platform	Target/Barrier Addressed	Key Result or Mechanistic Highlight	Ref.
Injured-tubule biomimetic targeting	KIM-1-homing bHDL nanoparticles	Damaged renal tubular niche	Co-delivered triptolide/nintedanib to remodel fibrotic niches while reducing systemic toxicity	[88]
Protected nucleic-acid delivery	Galactosamine-modified SSLNPs	siRNA degradation and tubular uptake	Protected CTGF siRNA and improved renal knockdown compared with naked siRNA	[89]
Chitosan gene carrier	HA-coated chitosan nanoparticles	CD44-mediated renal uptake	Delivered BMP7 or HGF/NK1 plasmids with antifibrotic gene expression	[90]
Megalin-mediated prodrug-like targeting	Metformin-grafted chitosan	Renal tubular accumulation	Increased kidney exposure while reducing systemic acidosis risk	[91]
Myofibroblast peptide targeting	Peptide-functionalized lipid-PLGA nanoparticles	Activated myofibroblasts in fibrotic lesions	Delivered sorafenib to collagen-producing cells and reduced matrix deposition	[92]
Enzyme-triggered release	LRG1-targeted DEN(NM) carrier	Apoptotic/fibrotic renal cells	Caspase-3-responsive nintedanib release increased renal accumulation and antifibrotic potency	[93]
Amino-acid-coded renal targeting	Poly-γ-glutamic acid or L-serine-modified polymers	Kidney distribution and tubular uptake	Amino-acid motifs improved renal accumulation and antisense/drug delivery efficiency	[94,95]
Prodrug-like enzyme activation	Kidney-targeted dendrimer-drug conjugate	Disease-associated renal enzymatic processing	Enzyme-activatable conjugate improved kidney-targeted therapy while limiting off-target exposure	[96]

Lipoproteins

High-density lipoproteins (HDL) possess an intrinsic affinity for renal tissues via scavenger receptor uptake, making them ideal candidates for “hijacking” endogenous pathways to deliver therapeutics to injured kidneys. Initial strategies utilized reconstituted HDL (rHDL) to leverage its natural tropism. In diabetic mice, rHDL administration significantly blunted albuminuria progression and glomerular injury. Histological evidence confirmed that rHDL reduced the accumulation of fibronectin and collagen IV, suggesting that supplementing the “good cholesterol” carrier itself confers renoprotection by stabilizing the glomerular filtration barrier.⁹⁷

To further refine precision towards damaged tubules, a biomimetic HDL (bHDL) system was engineered to exploit the pathological upregulation of KIM-1. Through KIM-1 mediated internalization, bHDL specifically delivered a synergistic combination of anti-inflammatory triptolide and anti-fibrotic nintedanib to injured epithelial cells. This “niche-remodeling” strategy effectively inhibited myofibroblast activation while mitigating the systemic toxicity of triptolide (Figure 6), demonstrating how biomimetic designs can transform toxic agents into safe, targeted therapies.⁸⁸

Figure 6.

Schematic illustration of TP/BIBF-bHDL preparation and KIM-1 mediated targeting of bHDL nanoparticles to injured renal tubules for CKD treatment. This schematic illustrates the fabrication of TP/BIBF-bHDL and their specific homing to injured renal tubules via the KIM-1 receptor, enabling precise remodeling of the fibrotic microenvironment. Reproduced from He et al, 2025⁸⁸ with permission from Nature Communications. Symbol legend: Solid black arrows indicate the experimental workflow, anatomical magnification, and targeted drug delivery; thin white arrows represent cellular endocytosis and subsequent intracellular biological processes; the thick grey arrow denotes the overall remodeling transition of the fibrotic niche. Red downward arrows (↓) signify a reduction or attenuation in inflammatory cytokine levels, fibroblast activation, immune cell infiltration, and ECM deposition; red lightning bolts denote injury stimuli causing tubule damage. Specific molecular and cellular components are defined in the embedded legends at the top right and bottom of the figure.

Liposomes

Liposomes, defined as spherical vesicles composed of phospholipid bilayers, offer a versatile scaffold for encapsulating diverse therapeutic payloads. Current engineering focuses on functionalizing the phospholipid surface to overcome solubility limits, systemic toxicity, and enzymatic degradation.

Nanoliposomes are critical for unlocking the potential of hydrophobic phytochemicals. For instance, silymarin, a potent antioxidant limited by poor solubility, was encapsulated in nanoliposomes. In diabetic nephropathy models, this formulation enhanced bioavailability and exerted a “dual-brake” effect: co-suppressing the TGF-β/Smad fibrotic axis and the JAK2/STAT3/SOCS1 inflammatory pathway. This multi-target intervention significantly improved podocyte survival and lipid profiles compared to the free drug.⁹⁸

Liposomes also serve as “safety shields” for potent epigenetic drugs. The BET inhibitor JQ1 halts fibrosis but is hindered by systemic side effects. JQ1-loaded liposomes were developed to optimize pharmacokinetics. A single administration early after ischemia-reperfusion injury was sufficient to target the kidneys and block BRD4, thereby halting the transcription of pro-inflammatory genes such as IL-6 and CCL2 and reducing immune infiltration. This strategy highlights the value of liposomes in widening the therapeutic window of epigenetic inhibitors.⁹⁹

To enable precision gene therapy, the phospholipid bilayer can be engineered for “steric stabilization” to protect fragile siRNA. A specialized sterically stabilized phospholipid nanocarrier (SSLNP) modified with galactosamine was developed to target asialoglycoprotein receptors on renal tubules. This carrier efficiently incorporated and protected siRNA targeting CTGF. Unlike naked siRNA which degrades rapidly, the siRNA-SSLNP system accumulated in renal tissues and successfully knocked down CTGF expression. This demonstrates that advanced phospholipid engineering can overcome the biological barriers restricting RNAi therapy in fibrosis.⁸⁹

While lipid-based systems excel in biocompatibility, they face a trade-off between structural stability and manufacturing complexity. Simple liposomes, such as those used for silymarin, are easy to produce but may leak cargo in circulation. Conversely, complex biomimetic constructs such as bHDL or SSLNPs offer superior targeting and stability but involve multi-step, costly synthesis. Future translation requires “hybrid lipid-polymer” systems that combine the biocompatibility of lipids with the structural rigidity of polymers to ensure scalable, stable, and precise delivery.

Polymers

Polymeric nanoparticles offer a broad spectrum of chemical diversity, enabling precise tuning of biodegradation, surface charge, and mechanical properties. Unlike lipids, polymers provide a more rigid scaffold for sustained drug release and are particularly advantageous for overcoming biological barriers, such as the intestinal epithelium for oral delivery or the glomerular filtration barrier for renal retention.

Chitosan Nanoparticles

Chitosan nanoparticles occupy a vanguard position within polymeric nanodelivery systems as ideal vectors for the targeted therapy of renal fibrosis, attributed to their superior biocompatibility, biodegradability, intrinsic mucoadhesion, and facile functionalization. Their cationic nature facilitates the efficient encapsulation of anionic therapeutic payloads via electrostatic interactions, whilst abundant surface amino and hydroxyl groups enable ligand-directed modification to achieve kidney-specific accumulation. Furthermore, the pH-responsive swelling behavior of chitosan nanoparticles permits precise, triggered drug release within the acidic microenvironment characteristic of fibrotic lesions, thereby significantly amplifying local therapeutic concentrations. These properties enable three distinct engineering paradigms: protective gene delivery, targeted chemical conjugation, and non-invasive oral therapy.

The cationic backbone of chitosan is ideal for condensing nucleic acids, but structural optimization is required for renal specificity. Geng et al engineered a low-molecular-weight chitosan-miRNA nanocomplex with optimized dimensions to facilitate glomerular filtration. This design protected miRNA inhibitors from nuclease degradation, enabling targeted silencing of miRNA-21 in tubular cells and suppressing the TGF-β1/Smad3 axis.¹⁰⁰ To further enhance uptake specificity, HA coating was employed to target CD44 receptors. This “ligand-shielded” chitosan vector successfully delivered BMP7 or HGF/NK1 plasmids, achieving high renal expression and significant fibrosis reversal.⁹⁰

Beyond physical encapsulation, chemical grafting transforms chitosan into a “smart” prodrug carrier. Exploiting megalin-mediated endocytosis, metformin-grafted chitosan nanoparticles achieved superior renal accumulation compared to free drug, exerting potent anti-fibrotic effects without systemic acidosis risk.⁹¹ Similarly, N-octyl-O-sulfated modification significantly enhanced the bioavailability of hydrophobic drugs like chrysophanol.¹⁰¹ Furthermore, the pH-sensitivity of chitosan enables microenvironment-responsive therapy. Li et al developed an N-acetylated-thiolated chitosan-cobalt complex that releases Co²⁺ specifically in the acidic fibrotic lesion.¹⁰² Qiao et al utilized coordination chemistry to assemble catechol-chitosan-metal nanocomplexes, which combined stability with pH-triggered release.¹⁰³ Notably, even unmodified crab shell chitosan nanoparticles demonstrated intrinsic reparative capacity comparable to stem cell therapy, highlighting the material’s inherent bioactivity.¹⁰⁴

Addressing the need for long-term CKD management, chitosan’s mucoadhesion is leveraged to construct non-invasive oral systems. Strategies to penetrate the mucus barrier include mPEG-modified chitosan, which enhanced the oral bioavailability of salvianolic acid B by more than three-fold.¹⁰⁵ More aggressively, Xiong et al developed brij-grafted chitosan nanoparticles (BC-NPs). By coordinating tight junction modulation with P-glycoprotein inhibition, this strategy amplified the absorption of berberine (BBR) by a factor of 4.4¹⁰⁶ (Figure 7).

Figure 7.

Enhanced intestinal absorption of berberine (BBR) via Brij-functionalized chitosan nanocarriers for improved oral therapy. This schematic illustrates how brij-chitosan nanoparticles (BC-NPs) enhance the oral bioavailability of berberine by reversibly modulating intestinal tight junctions (paracellular pathway) and inhibiting P-glycoprotein (P-gp)-mediated drug efflux (transcellular pathway). This strategy exemplifies a promising nano-enabled approach to overcome absorption barriers for orally administered agents in CKD management. Reproduced from Xiong et al, 2021¹⁰⁶ with permission from Carbohydrate Polymers. Symbol legend: Thick blue arrows indicate the nanoparticle synthesis workflow; solid yellow arrows represent the energy conversion from ATP to ADP and the subsequent P-gp-mediated drug efflux transport; the yellow cross (✕) placed over the transport arrow denotes the inhibition of this P-gp efflux pump; green spheres represent BBR molecules; purple wavy lines (top) represent the TPP crosslinker; multi-colored complex spheres illustrate the formulated BBR-BC-NPs; purple oval structures between epithelial cells represent tight junctions (TJs).

Advanced “piggybacking” strategies have also emerged. Hou et al encapsulated chitosan/alginate microgels within yeast cell walls to co-deliver probiotics and drugs, targeting both the kidney and the gut microbiome.¹⁰⁷ Similarly, Liu et al employed a bile acid-mimetic pathway using deoxycholic acid-modified chitosan to enhance intestinal uptake and escape lysosomal degradation.¹⁰⁸

Collectively, chitosan nanocarriers represent a versatile paradigm of “responsive precision” in renal fibrosis management, distinguishing themselves through the integration of mucoadhesive oral delivery, megalin-mediated active targeting, and pH-triggered release kinetics. Yet, clinical translation is impeded by significant chemistry, manufacturing, and controls (CMC) hurdles, particularly the batch-to-batch heterogeneity inherent to natural polymers and their undefined metabolic fates. To bridge this gap, future engineering must shift from trial-and-error to rational design, leveraging AI and organoid platforms to decipher structure-activity relationships. Furthermore, developing “hybrid architectures”—by merging chitosan with synthetic moieties—is essential to reconcile biological affinity with the manufacturing reproducibility required for clinical use.

Polyesters

Synthetic polyesters, prototyped by the FDA-approved PLGA, serve as the gold standard for biodegradable carriers. Their clinical relevance lies in their tunable degradation rates spanning weeks to months and the ability to encapsulate hydrophobic pharmacophores within a stable core. Current engineering focuses on exploiting “pathological permeability” via size control and optimizing surface chemistry for extended circulation.

Precise size engineering is critical for leveraging the “enhanced permeability and retention (EPR)-like” effect in injured kidneys. Studies utilizing PLGA-oltipraz nanoparticles with a diameter of approximately 100 nm revealed a preferential accumulation in the kidneys during the acute phase of IRI. This accretion exhibited a strong spatiotemporal correlation with the severity of injury. By specifically delivering the antioxidant oltipraz to TECs, this formulation exerted superior antioxidative potency evidenced by elevating SOD and reducing MDA, effectively mitigating early tubular necrosis and preventing long-term fibrotic sequelae.¹⁰⁹ Furthermore, extended retention is essential for sustained pathway inhibition.

PLGA-eleutheroside B nanoparticles with a diameter of approximately 128 nm demonstrated specific renal retention extending up to 7 days in UUO mice. Molecular docking and silencing experiments confirmed that the payload, eleutheroside B, binds directly to Smad3. This sustained delivery effectively blocked Smad3 phosphorylation, thereby downregulating α-SMA and collagen I expression even in established fibrosis.¹¹⁰

To address the full spectrum of the AKI-to-CKD transition, surface modification is employed to modulate pharmacokinetics and immune interactions. PEGylated bilirubin nanoparticles were constructed to overcome the solubility limits of bilirubin. Following intravenous administration, this “synthetic nanomedicine” showed marked renal uptake with negligible blood-brain barrier penetration, thereby reducing neurotoxicity risks. Administration during the acute window conferred a “biphasic protective effect”: it first arrested the acute inflammatory cascade by reducing ROS and TNF-α/MCP-1 and subsequently promoted tubular regeneration while inhibiting chronic fibrosis by Day 28. This underscores the capability of polymer-based systems to manage the complex temporal dynamics of renal disease.¹¹¹

While PLGA is celebrated for its biodegradability, its hydrolysis yields lactic and glycolic acids, which can locally lower the microenvironmental pH. In an already acidic fibrotic lesion, this “autocatalytic acidification” might exacerbate local inflammation or degrade acid-labile protein payloads. Future rational design should consider incorporating acid-neutralizing porogens within the polymer matrix to buffer the degradation microenvironment, ensuring optimal therapeutic safety.

Other Polymers

Beyond chitosan and polyesters, polymers such as dendrimers, coordination polymers, and biomimetic hybrids have been developed to address renal delivery barriers. Their designs can be grouped into three functions: compartment-specific targeting, microenvironment-responsive release, and management of systemic CKD complications.

Polymer architecture can be modified to target different renal cell populations and compartments. In the tubulointerstitium, Cheng et al used phage display to identify peptides that bind to MYFs. Incorporation of these peptides into lipid-PLGA nanoparticles directed sorafenib to fibrotic lesions and reduced collagen deposition.⁹² Zhang et al targeted leucine-rich α-2-glycoprotein 1 (LRG1) with an ET-peptide-modified carrier (DEN(NM)), achieving a fourfold increase in renal accumulation and caspase-3-triggered release of nintedanib in apoptotic cells.⁹³ For injured tubules, polydopamine (PDA)-polyethylenimine-L-serine-Klotho nanoparticles (PPSK NPs) used the affinity of PDA for KIM-1 to deliver Klotho plasmids and activate PPARα signaling¹¹² (Figure 8). Glomerular targeting requires carriers that can negotiate the filtration barrier. Cyclic RGD-functionalized dendrimers targeted αvβ3 integrin on podocytes for HDAC4 siRNA delivery,¹¹³ whereas α8 integrin antibody-decorated PLGA-liposome hybrids increased drug concentrations in the mesangial region sixfold.¹¹⁴ Physical guidance provides another option: a Fe₃O₄@mesoporous PDA system localized thrombolytic agents under an external magnetic field.¹¹⁵

Figure 8.

Targeted gene therapy using polydopamine (PDA)-polyethylenimine-l-serine-Klotho nanoparticles (PPSK NPs) to prevent AKI-CKD transition and renal fibrosis. This schematic illustrates the synthesis of PPSK NPs and their KIM-1-mediated targeted delivery of the Klotho gene to injured tubular epithelial cells (TECs). Sustained Klotho expression activates PPARα signaling, thereby enhancing fatty acid β-oxidation (FAO), reducing lipid accumulation, and ultimately protecting against fibrosis during the AKI-to-CKD progression. Reproduced from Li et al, 2025¹¹² with permission from Biomaterials. Symbol legend: Horizontal blue-gradient arrows indicate the nanoparticle synthesis and modification workflow, complemented by curved yellow and green arrows representing the functionalization of PEI 25K and L-serine, respectively; the lightning bolts denote acute renal injury stimuli; yellow Y-shaped structures on the TEC membrane represent KIM-1 receptors; intracellular purple arrows indicate sequential signaling cascades and metabolic pathways; red upward (↑) and blue downward (↓) arrows represent the upregulation/activation or downregulation/inhibition of corresponding genes, proteins, or metabolites; curved maroon arrows pointing outward at the top indicate the ultimate downstream therapeutic outcomes leading to the attenuation of renal fibrosis.

Targeting can also be encoded through polymer composition or disease-responsive cleavage rather than conventional ligand-receptor binding. A poly-γ-glutamic acid coating altered protein-corona formation and improved renal distribution and tubular uptake in diabetic nephropathy.⁹⁴ Modification of poly-L-lysine with L-serine similarly increased proximal-tubule accumulation.⁹⁵ Other approaches address glomerular transport or local activation. BMP7 nanocarriers enhanced glomerular transfection and promoted SOX9-dependent tubular regeneration,¹¹⁶ whereas enzyme-cleavable dendrimer-drug conjugates released their payload in response to renal disease-associated enzymes.⁹⁶ Together, these studies broaden the renal-targeting repertoire beyond receptor-mediated homing.

Polymer carriers can also be designed to respond to the fibrotic microenvironment while protecting labile payloads. pH-sensitive PDPA nanoparticles developed by Lee et al remained stable at physiological pH but dissociated under acidic conditions (pH 4.0–6.0), releasing nitric oxide donors that inhibited TGF-β signaling.¹¹⁷ Cationic polyethyleneimine protected miR-146a from nuclease degradation, enabling inhibition of NF-κB/TGF-β1 signaling.¹¹⁸ Formulation also improved the solubility and stability of small molecules: PLGA nanoparticles increased the accumulation of hydrophobic Gynostemma saponin XLIX by 3.2-fold,¹¹⁹ whereas PVP-modified curcumin-ruthenium nanodots combined ultrasmall size with colloidal stability and ROS scavenging.¹²⁰

Polymers may also be used to address extrarenal complications of CKD. To modulate uremic toxin-producing gut microbiota, Xu et al combined deoxycholic acid-chitosan-coated liposomes with an in situ gel. The formulation improved emodin bioavailability, prolonged colonic retention, and downregulated TLR4/NF-κB signaling.¹²¹ Lactate-chitosan nanoparticles administered by colonic perfusion reduced serum IL-6 by 48%, an effect associated with microbiota modulation.¹²² For secondary infection, polymer-coated Ga₂(HPO₄)₃ nanoparticles stabilized Ga³⁺ against hydrolysis and disrupted bacterial iron metabolism through a Trojan-horse mechanism.¹²³

Together, these systems illustrate how polymer design can support compartment-specific targeting, stimuli-responsive release, and management of selected extrarenal complications. Their increasing structural complexity, however, complicates CMC, including scale-up and batch reproducibility. Clinically oriented development should therefore favor the simplest architecture that retains the required targeting or therapeutic function.

Natural and Biologically Derived Nanoparticles

Distinct from synthetic constructs, biologically derived nanoparticles—spanning EVs, protein complexes, and melanin—possess an evolutionary advantage: intrinsic biocompatibility and innate biological coding. These systems are naturally “engineered” to traverse biological barriers, evade immune surveillance, and engage in precise intercellular communication, positioning them as privileged vectors for renal fibrosis therapy.

Extracellular Vesicles (EVs)

EVs mediate intercellular communication by transporting proteins, lipids, and nucleic acids within a lipid bilayer. Their use in renal fibrosis is being developed along three main lines: surface modification for renal targeting, cargo engineering, and strategies to prolong tissue retention.

Surface engineering can increase EV accumulation in injured kidney tissue. Tang et al used macrophage-derived microvesicles bearing αLβ2 and α4β1 integrins to target inflamed renal tissue and deliver dexamethasone (DEX)¹²⁴ (Figure 9). Renal endothelial cell-targeted EVs likewise reduced ischemic kidney injury.¹²⁵ Ji et al functionalized mesenchymal stem cell (MSC)-derived EVs with superparamagnetic iron oxide nanoparticles (SPIONs), enabling magnetic guidance of CHIP cargo to injured tissue.¹²⁶ Related biomimetic approaches use cell membranes rather than intact EVs; for example, platelet membrane-cloaked PLGA nanoparticles targeted injured vasculature and delivered TGF-β1 siRNA.¹²⁷

Figure 9.

Preparation of macrophage-derived microvesicle-loaded dexamethasone (MV-DEX) for targeted therapy of renal inflammation and fibrosis. This schematic illustrates the fabrication of MV-DEX and its mechanism of action. MV-DEX achieves kidney-specific targeting via LFA-1/VLA-4 integrins, enhances glucocorticoid receptor (GR) levels, and promotes intracellular dexamethasone (DEX) delivery, thereby potently attenuating renal inflammation and fibrosis with minimized systemic side effects. Reproduced from Tang et al, 2019¹²⁴ with permission from Theranostics. Symbol legend: Curved solid black arrows indicate the experimental isolation and therapeutic workflow loop; the dashed black arrow represents conventional systemic DEX treatment and its associated adverse clinical outcomes; the blue-shaded cone signifies the schematic magnification of the localized inflammation-targeting mechanism; red upward (↑) and downward (↓) arrows denote a significant increase or decrease in clinical parameters or intracellular protein/drug concentrations; the lightning bolts represent renal injury stimuli; the dark red T-shaped arrow indicates the transcriptional suppression of NF-κB mediated by the GR, whereas the red cross (×) represents the subsequent blockade of downstream pro-inflammatory cytokine and chemokine production. Detailed molecular structures are explicitly defined in the embedded legend at the bottom.

Cargo selection determines the therapeutic activity of EVs. Native exosomes from parietal epithelial cells delivered let-7b-5p and limited fibrosis;¹²⁸ EVs from regenerative-associated cells carried a miRNA profile that inhibited TGF-β signaling;¹²⁹ and human umbilical cord MSC-derived exosomes promoted YAP degradation.¹³⁰ Cargo engineering further expanded these effects: exosomal delivery of a super-repressor IκBα inhibited NF-κB signaling in ischemic kidneys,¹³¹ whereas kidney MSC-derived EVs engineered to carry erythropoietin improved renal anemia in mice with CKD.¹³² Pretreating the parent MSCs with CeO₂ nanoparticles or melatonin also enhanced the anti-inflammatory and antifibrotic activity of the released exosomes.^133,134

Local retention remains a separate challenge. Incorporating MSC-derived EVs into an injectable collagen matrix prolonged renal retention and enhanced therapeutic effects in experimental acute kidney injury.¹³⁵

EV biology also presents a safety concern because endogenous vesicles may propagate disease signals. In diabetic kidney disease, EVs released from injured tubular cells transferred noncoding RNAs that stabilized HIF-1α in macrophages and promoted inflammation.¹³⁶ Therapeutic development should therefore evaluate both the activity of administered EVs and their potential effects on pathological intercellular communication.

Protein Complexes

Protein complex nanoparticles occupy a unique niche characterized by a distinct dichotomy: they function as innovative delivery vectors overcoming pharmacological barriers, yet also appear as endogenous mediators driving disease progression.

Albumin nanoparticles effectively resolve the “solubility-stability” bottleneck. Huang et al engineered BSA nanoparticles loaded with the Ras inhibitor farnesyl thio-salicylic acid (FTS). By improving the solubility of FTS and leveraging gp60 receptor-mediated transcytosis, this system achieved preferential renal tropism. It effectively abrogated EMT and fibroblast activation by intercepting the Ras/Raf1/p38 axis.¹³⁷

Conversely, endogenous protein complexes can catalyze fibrosis. Yoon et al identified calciprotein particles—nanoparticles formed by calcium phosphate and serum proteins in CKD patients—as active pathogens. These particles instigate EMT in TECs by activating calcium-sensing receptors (CaSR) and the CDC42 cascade. Using a high-fidelity 3D TEC model, this study elucidated how protein-mineral complexes drive fibrosis, offering a novel target for intervention.¹³⁸

Melanin Nanoparticles (MNPs)

MNPs distinguish themselves through their intrinsic photoacoustic properties and radical scavenging capacity, representing the ideal candidate for “Theranostic Integration”.

Li et al engineered PEGylated MNPs to encapsulate curcumin. Possessing an ultrasmall diameter of approximately 10 nm, these particles achieved efficient glomerular filtration and tubular accumulation. Their intrinsic signal enabled real-time photoacoustic imaging to monitor intrarenal drug distribution. Therapeutically, the anti-inflammatory melanin core synergized with the antioxidant curcumin cargo to exert potent anti-fibrotic efficacy. This platform exemplifies how natural pigments can be repurposed into sophisticated nanomedicines for precision management.¹³⁹

Collectively, biologically derived nanoparticles leverage evolutionary adaptations—such as intrinsic barrier traversability and immune evasion—to achieve superior targeting. However, clinical translation is obstructed by biogenic heterogeneity: unlike synthetic polymers, natural carriers suffer from batch-to-batch inconsistencies that complicate quality control. Furthermore, their potential to transmit pathological signals necessitates rigorous safety evaluation. To overcome these barriers, the field is shifting towards “Engineering Cellular Factories” and “Semi-Synthetic Hybrids”, aiming to standardize production via synthetic biology without compromising the innate therapeutic potency of these biological vectors.

Composite Nanomaterials

Composite nanomaterials represent the apex of nanotherapeutic engineering, transcending monomeric limitations by integrating inorganic moieties with organic matrices into multifunctional hybrid architectures. These systems are designed not merely as carriers, but as “intelligent therapeutic platforms” that leverage the distinct physicochemical properties of each component—magnetic responsiveness, acoustic sensitivity, or biological affinity—to achieve synchronized spatiotemporal control over drug release and multimodal intervention in the inflammation-fibrosis cascade.

The “core-shell” design strategy enables the segregation of incompatible payloads and the integration of multiple targeting ligands. Fang et al engineered a sophisticated Gold-Lipid Nanohybrid targeting MCs. This architecture features an AuNP core loaded with TGF-β1 siRNA encapsulated within a phospholipid shell carrying DEX, surface-decorated with anti-α8 integrin antibodies. This system achieved a “dual modulation” effect: simultaneously silencing pro-fibrotic TGF-β1 and suppressing pro-inflammatory TNF-α cytokines, significantly ameliorating glomerulonephritis pathology.¹⁴⁰ Similarly, Liu’s group utilized magnetic albumin nanoparticles to achieve actuated enrichment in renal tubules under an external magnetic field. Mechanistically, they reversed albumin-induced injury by reactivating the Rab7-mediated autophagy pathway, highlighting the potential of magnetically responsive composites in modulating intracellular trafficking.¹⁴¹

Coordination chemistry offers a precise method to construct “supramolecular” nanostructures that respond to specific microenvironmental triggers. Tan et al constructed gold-cobalt nanostructures via the coordination of glutathione-modified AuNPs with Co²⁺ ions. These assemblies remain stable in blood but undergo rapid disassembly within the acidic, GSH-rich lysosomal compartment of fibrotic tissues. The liberated Co²⁺ acts as a hypoxia-mimetic agent, activating the HIF-1α/miR-29c axis. This specific restoration of miR-29c effectively mitigated interstitial fibrosis, with preferential accumulation observed in proximal tubules.⁶²

Advanced engineering allows for “systems-within-systems” designs to overcome macroscopic biological barriers or enable physical triggering. Sun’s team developed a “nanoparticle-in-microcapsule” hierarchical system to address the poor oral bioavailability of hydrophobic drugs. By embedding tanshinone IIA-loaded nanoparticles within emodin-containing microcapsules, this architecture facilitates sequential release and enhances transmembrane transport, rectifying the pharmacokinetic limitations of combinatorial herbal therapy.¹⁴² Furthermore, Wei et al designed an ultrasound-responsive microbubble-nanoparticle composite. Upon acoustic triggering, the oscillation of SonoVue microbubbles enhances tissue permeability, facilitating the precise release of rosiglitazone-loaded PLGA nanoparticles. This “physical-biological” synergy significantly attenuated fibrosis via PPARγ pathway activation.¹⁴³

In summary, composite nanomaterials surmount the functional ceilings of monomeric carriers through three strategic integrations: Structural Hybridization such as core-shell architectures for multi-drug codelivery; Stimuli-Responsive Coordination for logic-gated release; and Physical-Biological Coupling via magnetic or acoustic actuation for active spatiotemporal control. However, “Complexity” is the Achilles’ heel of these advanced systems. The multi-step synthesis required to assemble these hierarchical structures introduces significant challenges in reproducibility and scale-up. Future translation efforts must prioritize “Modular Assembly” techniques—such as microfluidic synthesis—to ensure batch-to-batch consistency, alongside rigorous long-term biosafety evaluations of the inorganic components to preclude heavy metal accumulation toxicity.

Other

Beyond canonical paradigms, a vanguard generation of nanomaterials has demonstrated breakthrough potential. These systems offer decisive advantages in circumventing systemic toxicity and optimizing the pharmacokinetics of natural products. Furthermore, they serve as critical tools for interrogating the complex, sometimes paradoxical, signaling networks underlying renal fibrosis.

Biomimetic viral vectors achieve precision transduction by exploiting evolutionary entry kinetics to access intracellular targets. Fleischmann et al engineered virus-mimetic nanoparticles (VNPs) to encapsulate the soluble guanylate cyclase (sGC) activator cinaciguat. Unlike systemic administration, which causes severe hypotension, these VNPs specifically targeted glomerular MCs by mimicking viral entry kinetics. This strategy enhanced sGC stabilization and cGMP signaling by 4–5 fold, effectively abrogating non-canonical TGF-β signaling and fibrogenic remodeling in DKD models. This demonstrates that biomimetic vectors can revitalize “hemodynamically risky” drugs for precision renal therapy.¹⁴⁴

Nanocrystal and polymer technologies act as critical enablers for hydrophobic phytochemicals. Lu et al developed polymeric quercetin nanoparticles (Que-NP) to overcome solubility barriers. In sepsis-induced AKI, this formulation activated Sirt1 to quench NF-κB phosphorylation, preserving renal function.¹⁴⁵ Crucially, Sánchez-Jaramillo’s team demonstrated a “dose-sparing effect”: Que-NPs achieved anti-fibrotic efficacy comparable to high-dose free quercetin but at significantly lower concentrations, validating that nanoscale formulation can maximize therapeutic indices.¹⁴⁶ Similarly, Yang et al engineered crocetin-loaded PLGA nanoparticles. These particles exhibited superior renal accumulation in DKD models, effectively downregulating PKC and NF-κB pathways to mitigate inflammation and fibrosis.¹⁴⁷

Advanced carriers further enable multi-modal intervention and reveal pathway complexities. Liu et al constructed a nanocrystal-based co-delivery platform loading indomethacin and uricase. This system addressed the “inflammation-metabolism” axis in hyperuricemic nephropathy, simultaneously lowering uric acid levels and mitigating synovial/renal inflammation.¹⁴⁸ However, nanomedicine also serves as a “functional probe” to uncover paradoxical signaling. Koike’s group utilized JAK inhibitor-loaded nanoparticles to intervene in UUO, unexpectedly finding that inhibiting the JAK/STAT pathway exacerbated fibrosis. Mechanistic analysis revealed that STAT3 activation is required for MMP-2 expression to degrade excess matrix. This finding serves as a crucial warning: not all upregulated pathways in fibrosis are purely pathogenic; some, like JAK/STAT, may facilitate compensatory repair.¹⁴⁹

In summary, these emerging platforms broaden the therapeutic horizon beyond traditional delivery: VNPs unlock “undruggable” intracellular targets via viral mimicry, while nanocrystal technology revitalizes natural products by resolving solubility bottlenecks. Most importantly, nanomedicine acts as a “functional probe”. As demonstrated by the paradoxical outcomes of JAK inhibition, the ability of nanoparticles to precisely perturb signaling nodes helps decipher the nuanced balance between profibrotic drive and reparative homeostasis. Future translation depends not only on optimizing carrier physics but also on deeply validating the biological logic of the molecular targets they carry. These examples, together with EV-based biomimetic systems and composite nanoplatforms discussed above, highlight a second design trajectory in which biological homing, physical actuation, and hybrid material assembly are combined to overcome renal delivery barriers (Table 4).

Table 4.

Biologically Derived, Composite, and Emerging Nanoplatforms: Biomimetic Targeting and Translational Design Decisions

Design Decision	Representative Platform	Target/Barrier Addressed	Key Result or Mechanistic Highlight	Ref.
Platelet-membrane vascular homing	Platelet membrane-cloaked PLGA/TGF-β1 siRNA	Injured renal vasculature	Improved renal accumulation and silenced TGF-β1/Smad3 signaling in UUO/IRI models	[127]
Magnetic EV guidance	SPION-functionalized MSC-EVs carrying CHIP	Actuated delivery to injured loci	Promoted Smad2/3 degradation through CHIP-mediated ubiquitination	[126]
Immune-cell chemotaxis	Macrophage-derived MV-DEX	Inflamed renal foci	Used LFA-1/VLA-4 interactions for kidney-specific DEX delivery	[124]
Engineered anti-inflammatory EV cargo	Exosomal super-repressor IκBα	NF-κB-driven ischemic inflammation	Suppressed inflammatory signaling and protected against kidney ischemia-reperfusion injury	[131]
Regenerative EV engineering	EPO-expressing kidney MSC-EVs and hucMSC exosomes	CKD anemia and profibrotic YAP signaling	Improved renal anemia or attenuated fibrosis through YAP degradation pathways	[130,132]
Endothelial-cell-targeted EVs	Renal endothelial cell-targeted EVs	Microvascular injury	Protected against ischemic kidney injury by enhancing vascular-directed vesicle delivery	[125]
Composite active targeting	Anti-α8 integrin Au-lipid hybrid	Mesangial inflammation and fibrosis	Co-delivered DEX and TGF-β1 siRNA for dual anti-inflammatory/antifibrotic action	[140]
Physical triggering	Ultrasound microbubble-PLGA composite	Tissue permeability and local release	Acoustic triggering enhanced rosiglitazone delivery and PPARγ-mediated antifibrotic effects	[143]
Viral mimicry	Virus-mimetic cinaciguat nanoparticles	Mesangial intracellular sGC/cGMP signaling	Targeted MC delivery reduced hypotension risk while suppressing TGF-β pathway activity	[144]

Avoiding Hepatic Uptake and Ensuring Safe Renal Clearance

After systemic administration, renal nanomedicines compete with hepatic and splenic sequestration. Opsonization and protein-corona formation promote uptake by Kupffer cells and splenic macrophages, reducing delivery to renal lesions and increasing off-target exposure.^150–153 Biodistribution is influenced by hydrodynamic diameter, surface charge, ligand density, and colloidal stability.^154,155 Strategies to limit nonspecific hepatic uptake include near-neutral or zwitterionic surfaces, optimized PEGylation, and biomimetic coatings such as albumin or HDL. Targeting ligands must be balanced against the need to preserve low-fouling surface properties during circulation.

Clearance imposes a complementary design constraint. Ultrasmall constructs below the glomerular filtration threshold may be rapidly excreted, but very short circulation times can limit lesion exposure.^156,157 Larger carriers may show greater retention in inflamed kidneys; however, they should degrade into renally excretable fragments or endogenous metabolites, particularly in patients with reduced GFR.^154,156 This consideration is especially important for inorganic systems containing Au, Ag, Mn, or silica because persistent material can accumulate in the kidney, liver, or other organs. Potential solutions include biodegradable polymers, magnesium-based reservoirs, naturally derived carriers such as EVs, and stimulus-cleavable hybrid structures.

We therefore propose evaluating renal nanomedicines within a delivery-clearance framework rather than by kidney accumulation alone. Relevant measures include the liver-to-kidney exposure ratio, the metabolic and urinary fate of carrier byproducts, clearance across CKD-relevant GFR ranges, and residual tissue burden after repeated dosing.^150,154,156 These endpoints should be incorporated early in preclinical development through serum-protein corona assays, macrophage uptake models, kidney-on-a-chip systems, and appropriately designed biodistribution studies.

Conclusions and Outlook

Renal fibrosis is a common structural endpoint of CKD, but therapeutic opportunities vary by cell type, renal compartment, and disease stage. The design principles reviewed here connect these biological differences to tunable material properties. Particle size can be adjusted for glomerular filtration or prolonged tissue retention; surface charge and protein-corona interactions can influence hepatic and renal distribution; and cleavable linkers can release cargo in acidic, oxidative, or hypoxic fibrotic microenvironments.

In practical terms, the renal nanomedicine toolkit comprises complementary carrier classes and targeting strategies: biodegradable polymer and lipid systems, renal-clearable ultrasmall inorganic nanozymes, biomimetic EVs, and ligands that direct payloads to injured tubules, activated mesangial cells, or myofibroblasts.

Three platform classes merit particular attention for translation, although none is universally optimal. Renal-clearable ultrasmall ceria nanoclusters combine catalytic ROS scavenging with urinary elimination and may be most useful in acute inflammatory injury or the AKI-to-CKD transition; rapid clearance, however, may limit their use in chronic disease. Biomimetic lipid nanoparticles, including KIM-1-targeted bHDL, can protect potent payloads and improve renal delivery, but complex surface functionalization can hinder scalable and reproducible manufacturing. Engineered EVs offer biocompatibility and endogenous homing properties, yet source-dependent heterogeneity and batch variability remain major barriers. Semi-synthetic EV hybrids may provide one route to greater manufacturing control.

These limitations are primarily challenges in materials science and pharmaceutical engineering. Candidate materials should have defined degradation and elimination pathways, tolerate sterilization and storage, and be amenable to scalable synthesis. Safety studies should extend beyond short-term renal function to assess long-term distribution in the liver, spleen, brain, and other organs, as well as altered clearance at low GFR.

Nanomedicine is therefore most useful when the carrier is selected for a specific biological and pharmacokinetic problem rather than applied as a generic delivery platform. A clinically credible system should combine selective renal exposure, an appropriate payload, reproducible manufacture, and measurable clearance. Meeting these criteria could translate advances in fibrosis biology into interventions that slow CKD progression, support renal repair, and enable more precise patient selection.

Funding Statement

This work was supported by the Jilin Provincial Science and Technology Development Program Project [Grant No. 20260205014GH].

Abbreviations

CKD, chronic kidney disease; RASI, renin-angiotensin system inhibitors; SGLT2, sodium-glucose cotransporter 2; TECs, tubular epithelial cells; MYFs, myofibroblasts; NETs, neutrophil extracellular traps; ECM, extracellular matrix; CTGF, connective tissue growth factor; α-SMA, alpha-smooth muscle actin; MMT, macrophage-to-myofibroblast transition; EndoMT, endothelial-to-mesenchymal transition; EMT, epithelial-to-mesenchymal transition; System Xc-, the cystine/glutamate antiporter; DKD, diabetic kidney disease; MCs, mesangial cells; iNOS, inducible nitric oxide synthase; eGFR, estimated glomerular filtration rate; GZMB, granzyme B; ROS, reactive oxygen species; FAO, fatty acid β-oxidation; miRNAs, microRNAs; PTEN, phosphatase and tensin homolog; lncRNAs, long non-coding RNAs; ceRNAs, competitive endogenous RNAs; MRAs, mineralocorticoid receptor antagonists; FSGS, focal segmental glomerulosclerosis; MSCs, mesenchymal stem cells; EVs, extracellular vesicles; RNAi, RNA interference; LNPs, lipid nanoparticles; UUO, unilateral ureteral obstruction; AuNPs, gold nanoparticles; AgNPs, silver nanoparticles; Mg²⁺, magnesium ions; Mg(OH)₂, magnesium hydroxide; PLGA, poly(lactic-co-glycolic acid); EPR, enhanced permeability and retention; magnesium hydride; MgH₂, CeO₂ NPs, cerium oxide nanoparticles; IRI, ischemia-reperfusion injury; NCs, ultra-small ceria nanoclusters; ZnO NPs, zinc oxide nanoparticles; Mn₃O₄ NPs, manganese oxide nanoparticles; C-Mn₃O₄ NPs, citrate-functionalized Mn₃O₄ NPs; SiO₂ NPs, silica nanoparticles; MTX, methotrexate; AKI, acute kidney injury; Se, selenium; Se@SiO₂, selenium-silica nanospheres; GPx, glutathione peroxidase; BSA, bovine serum albumin; Ch-SeNPs, chitosan-stabilized SeNPs; GQDs, graphene quantum dots; PFPs, perfluorocarbon nanoparticles; TRPC5, transient receptor potential channel 5; HDL, high-density lipoproteins; rHDL, reconstituted HDL; bHDL, biomimetic HDL; SSLNP, sterically stabilized phospholipid nanocarrier; HA, hyaluronic acid; BC-NPs, brij-chitosan nanoparticles; BBR, berberine; LRG1, leucine-rich α-2 glycoprotein 1; DEN(NM), ET-peptide-modified carrier; PDA, polydopamine; PPSK NPs, PDA-polyethylenimine-L-serine-Klotho nanoparticles; NO, nitric oxide; MV-DEX, microvesicle-loaded dexamethasone; DEX, dexamethasone; FTS, farnesyl thio-salicylic acid; CaSR, calcium-sensing receptors; MNPs, Melanin Nanoparticles; VNPs, virus-mimetic nanoparticles; sGC, soluble guanylate cyclase; Que-NP, polymeric quercetin nanoparticles; CMC, chemistry, manufacturing, and controls; SPIONs, superparamagnetic iron oxide nanoparticles.

Disclosure

The authors report no conflicts of interest in this work.