Iron homeostasis: effects of different levels of protein iron on placental iron handling in sows.

ABSTRACTMHC class I (MHC‐I) cross‐presentation involves final proteolytic peptide processing by the endosomal insulin‐regulated aminopeptidase (IRAP). Reasoning that analysis of the IRAP‐proximal proteome may inform about dynamic remodeling of a key cross‐presentation compartment during antigen uptake, we developed a proximity biotinylation system by expressing an IRAP‐TurboID fusion protein in MuTuDCs, a cell line resembling murine type 1 conventional dendritic cells. Analysis of luminal proteins associated with IRAP at steady state and during phagocytosis revealed a massive shift upon uptake of yeast but not apoptotic cells, favoring enrichment of antigen‐processing machinery, MHC‐I molecules, and proteins involved in ER‐associated folding and trafficking. Importantly, Sec22b modulated this proteomic landscape, promoting the localization of MHC‐I cross‐presentation proteins (e.g., MHC‐I, Tap1, Wdfy4, transferrin receptor) to the IRAP environment, while its absence favored MHC‐II and ER‐related proteins, suggesting a Sec22b‐dependent dichotomy between pathways favoring cross‐presentation versus antigen degradation. Intriguingly, uptake of apoptotic cells failed to promote cross‐presentation but induced two proteins related to immune tolerance, suggesting potential adaptation of proteome modulation to the outcome of antigen presentation. These data suggest that IRAP+ endosomes serve as adaptive hubs integrating secretory and endocytic pathways, with Sec22b acting as a key determinant in tailoring this compartment for MHC‐I‐mediated cross‐presentation.

LncRNA SNHG6 attenuates ferroptosis in high glucose-treated renal tubular epithelial cells by stabilizing YY1 to activate the PI3K/AKT/GSK-3β pathway.

Molecular code of ferroptosis: emerging multi-dimensional modifications and therapeutic targets in hepatic disorders.

Myocardial ischemia-reperfusion injury (MI/RI) refers to the deterioration of cardiac function after restoring ischemic myocardium perfusion. Stem cell exosomes have produced unique advantages in treating MI/RI. However, the roles of exosomal microRNA-223-3p (miR-223-3p) from adipose-derived stem cells (ADSCs) on MI/RI are still unclear. This study aimed to investigate the effects of exosomal miR-223-3p from ADSCs on hypoxia/reoxygenation (H/R)-induced H9c2 cell injuries. Our findings indicated that the separated ADSC-derived exosomes (ADSC-Exo) were spherical, with a complete cell membrane, an average diameter of 110 nm, and CD9 and CD63 expression. ADSC-Exo increased the cell viability, proliferation, glutathione (GSH) level, and glutathione peroxidase 4 (GPX4) and miR-223-3p expression and decreased the apoptosis, reactive oxygen species (ROS), malondialdehyde (MDA), and Fe2+ levels and acyl-CoA synthetase long chain family member 4 (ACSL4) and transferrin receptor (TFRC) expression of H9c2 cells. Overexpressing exosomal miR-223-3p from ADSCs further strengthened the effects of ADSC-Exo on H9c2 cells. Overexpressing TFRC in H9c2 cells effectively reversed the effects of miR-223-3p overexpressed ADSC-Exo on H9c2 cells. In addition, miR-223-3p targeted and negatively regulated TFRC. This study confirmed that exosomal miR-223-3p from ADSCs alleviated H/R-induced ferroptosis of H9c2 cells by inhibiting TFRC, providing a novel target and pathway for the clinical treatment of MI/RI.

The incidence of primary liver cancer is increasing annually, with extremely high mortality and suboptimal therapeutic outcomes. The inefficient presentation of tumor antigens and low infiltration of specific cytotoxic T lymphocytes (CTLs) result in insufficient immunogenicity, which limits the efficacy of immunotherapy. Despite the popularity of immune checkpoint inhibitors (ICIs), insufficient immune activation means only a small subset of hepatocellular carcinoma (HCC) patients exhibit clinical responses to ICIs, showing significant inter-individual variability. The activation of the cyclic GMP-AMP synthase(cGAS)- stimulator of interferon genes(STING) pathway initiates the expression of type I interferons (IFNs) and inflammatory cytokines, promoting the formation of a pro-inflammatory environment at the tumor site. This pathway enhances anti-tumor immune responses by facilitating antigen processing and presentation, T cell priming and activation, and remodeling of the immunosuppressive microenvironment. Our research found that cucurbitacin B (CuB), a natural component derived from traditional Chinese medicine, had significant anti-hepatocellular carcinoma properties and exerted anti-tumor effects through the cGAS-STING pathway. Specifically, CuB regulated ferroptosis by down-regulating the expression of Solute Carrier Family 7 Member 11 (SLC7A11) and Glutathione Peroxidase 4 (GPX4) and upregulating the expression of Transferrin Receptor Protein 1 (TFR1) and Long-chain Acyl-CoA Synthetase 4 (ACSL4). These actions involved lipid substrates, iron ion homeostasis, and antioxidant defense systems. The release of mitochondrial DNA (mtDNA) triggered by ferroptosis activated the cGAS-STING immune signaling pathway, leading to the up-regulation of cGAS, phosphorylated STING (p-STING), phosphorylated TANK-binding kinase 1 (TBK1), phosphorylated Interferon regulatory factor3 (IRF3), and Interferon-β (IFN-β). This cascade activation pattern provides new insights into the drug treatment of tumors.

Aim . To assess the prevalence of iron deficiency in patients with chronic thromboembolic pulmonary hypertension (CTEPH), their impact on survival and functional status, and to identify the most informative indicator for assessing iron deficiency (ID) in this group. Material and methods . The study included 283 patients with a newly diagnosed CTEPH (mean age 56,0 [44,0; 67,0] years, 47% men). All patients underwent iron metabolism (serum iron, transferrin, serum ferritin, soluble transferrin receptors), proinflammatory cytokine (interleukin (IL)-6, -8, -10 and monocyte chemotactic protein (MCP-1)), hepcidin, and endothelin-1 tests. The control group consisted of 24 healthy donors (mean age, 58 [39; 64] years; men, 46%). Results . The prevalence of anemia was 17% (n=48), and the proportion of patients with iron deficiency anemia was 78% (n=37). No differences were found in pulmonary circulation hemodynamics or functional status when comparing patients with and without anemia, nor was there an effect of anemia on three-year patient survival. An increase in the level of C-reactive protein, IL-10 and MCP-1 in patients with CTEPH and their association with iron metabolism parameters were demonstrated. Depending on the criteria used, the prevalence of ID ranged from 24,5% to 69,1%. For the transferrin saturation, a weak direct correlation was established with such prognostic indicators as the 6-minute walk test (r=0,21; p=0,032), peak oxygen consumption (r=0,26; p=0,044) and mixed venous oxygen saturation (r=0,34; p=0,040). In addition, significant differences in the severity of CTEPH were revealed when dividing into groups according to transferrin saturation value of more/less than 20%. Three-year survival analysis in patients with CTEPH revealed significant differences in survival rates for ID criteria based on soluble transferrin receptor levels (>4,4 for men; >5,0 for women (Roche Diagnostics)) and our proposed ID criteria (serum ferritin (SF) <30 μg/L or 30<SF<299 μg/L with transferrin saturation <20%). Conclusion . Evidence was obtained to support the diagnostic value of transferrin saturation for diagnosing ID in patients with CTEPH, and supplemented ID criteria were proposed for this subgroup of patients with pulmonary hypertension.

Many transmembrane (TM) signaling receptors undergo essential posttranslational modification in the Golgi prior to their delivery to the plasma membrane (PM). Whether and how the passage and accompanied modification of these proteins across the Golgi is controlled remains unclear. Here, we show that leptin receptor overlapping transcript (LEPROT) and LEPROT-like 1 (LEPROTL1) regulate TM receptor activation by securing their sufficient Golgi retention. LEPROTs localize to cis and medial Golgi in a coat protein complex I (COPI)-dependent manner. LEPROTs interact directly with COPI coats and simultaneously engage a variety of integral membrane proteins with relatively long TM domains at acidic pH. Deletion of LEPROTs in cells causes expedited release of TM receptors transiting through the Golgi. Loss of LEPROTs dysregulates receptor signaling activity, including that of epidermal growth factor receptor (EGFR) and transferrin receptor (TFRC), due to defective modification. Collectively, LEPROTs serve as a class of COPI cargo receptors for TM receptors, ensuring adequate preparation, which is vital for subsequent action on the PM.

Introduction Calcium and iron are essential bioelements regulating neuronal function and survival. Dysregulation of calcium signaling and iron homeostasis is implicated in Alzheimer’s disease (AD), contributing to oxidative stress, synaptic dysfunction, and neurodegeneration. Previously, using in vitro cell-based models and transgenic mice, we demonstrated that CAMKK2, a calcium/calmodulin-dependent protein kinase, regulates iron transport via transferrin (TF) and transferrin receptor (TFRC). While excessive iron deposition is a hallmark of AD brains, the mechanisms underlying its dysregulation remain poorly understood. In a prior study of postmortem temporal cortex tissues, we showed that CAMKK2/TF/TFRC protein levels were significantly reduced in AD compared to cognitively normal (CN) individuals, and that increased iron accumulation in AD correlated with reduced TF/TFRC levels. This follow-up study aimed to assess CAMKK2/TF/TFRC protein levels in hippocampal tissues - an early site of AD pathology - and examine their relationship with tau (MAPT) aggregation in AD, Parkinson’s disease (PD), and frontotemporal dementia (FTD). Methods Postmortem hippocampal tissues from 29 CN individuals and patients diagnosed with AD/FTD/PD (N = 73/7/9 respectively) were analyzed. CAMKK2/TF/TFRC/MAPT levels were quantified using Western blotting. Correlation analyses evaluated associations among these proteins and with age, sex, and postmortem interval (PMI). Isoelectric focusing (IEF) was used to assess post-translational modifications of CAMKK2 and TF. Results CAMKK2 and TF levels were significantly reduced in AD, FTD, and PD hippocampi compared to CN controls. TFRC reduction was specific to late onset AD, suggesting a later event. MAPT levels were significantly elevated in AD, with high molecular weight smears indicating tau aggregation. CAMKK2 and MAPT were positively correlated in CN but not in AD, indicating disease-specific disruption. TF and CAMKK2 were also positively correlated in CN but attenuated in AD. No significant changes in CAMKK2 or TF charge states were detected. Discussion CAMKK2 downregulation and impaired iron transport appear to be shared features across multiple neurodegenerative diseases, but their decoupling from tau pathology seems specific to AD. These findings position CAMKK2 as a molecular gatekeeper linking calcium signaling, iron metabolism, and tau aggregation. Future studies should focus on elucidating the mechanisms underlying CAMKK2 downregulation to better understand its role in AD pathogenesis.

Lactoferrin (LF), a major iron-binding protein, has been proposed as a delivery system through which iron can be absorbed from human milk to enhance iron status. However, the effects of combining LF with iron on iron status in children remain to be comprehensively evaluated. To investigate whether iron combined with bovine LF is more effective than iron alone in improving iron status in children with or without anemia, thereby clarifying the potential adjuvant role of LF in anemia therapy. A systematic search of PubMed, Web of Science, Embase, and the Cochrane Library was conducted for clinical trials published up to December 2024. Population characteristics and mean difference (MD) in iron metabolism indicators were extracted and analyzed. A random-effects model was used to estimate pooled effects. A total of 160 studies were identified, of which 10 were included in qualitative synthesis and 8 in meta-analysis. Overall, LF supplementation showed an additional effect on serum ferritin compared with iron alone (MD, 3.52 µg/L; 95% CI, 0.66-6.38; P = .02). However, no significant effects were observed on hemoglobin, serum iron, or serum transferrin receptor levels (all P > .05). The combination of LF and iron did not improve hemoglobin status in children with or without anemia compared with iron alone, but it modestly increased serum ferritin. These findings suggest that LF may play a specific adjuvant role in regulating iron storage rather than enhancing hemoglobin levels. PROSPERO registration no. CRD42021259371.

Lactoferrin-modified niclosamide lipid nanocarriers reprogram ferroptosis and antioxidant networks for breast cancer suppression.

Novel duck orthoreovirus (NDRV) infection induces severe splenic necrosis in ducks, resulting in a cascade of detrimental consequences, including immunosuppression, secondary infections, and diminished vaccine efficacy. Avian orthoreovirus (ARV) exhibits high tropism for macrophages, with splenic macrophages being identified as the primary target cells of NDRV. Although ferroptosis has been implicated in this pathological process, the molecular mechanism underlying NDRV‐induced cellular damage remains poorly elucidated. In this study, an in vitro model of NDRV infection was established using HD11 cells to systematically investigate its effect on ferroptosis and the associated mechanisms. Our results indicate that NDRV infection triggers ferroptosis and markedly elevates intracellular Fe2+ levels. Mechanistically, NDRV upregulates transferrin receptor 1 (TfR1), thereby enhancing iron uptake, promoting iron accumulation, and ultimately inducing ferroptosis. This study is the first to reveal that NDRV induces macrophage ferroptosis by hijacking cellular iron metabolism, providing a theoretical foundation for understanding the mechanism through which NDRV infection mediates splenic necrosis and immune cell injury.

The blood-brain barrier (BBB) restricts therapeutic delivery to the central nervous system (CNS), hindering the treatment of neurological disorders, such as Alzheimer's disease, Parkinson's disease, brain cancers, and stroke. Aptamers, short single-stranded DNA or RNA oligonucleotides that can fold into unique 3D shapes and bind to specific target molecules, offer high affinity and specificity, low immunogenicity, and promising BBB penetration via receptor-mediated transcytosis targeting receptors such as the transferrin receptor (TfR) and low-density lipoprotein receptor-related protein 1 (LRP1). This review examines aptamer design through the Systematic Evolution of Ligands by Exponential Enrichment (SELEX) and its variants, mechanisms of BBB crossing, and applications in CNS disorders. Recent advances, including in silico optimization, in vivo SELEX, BBB chip-based MPS-SELEX, and nanoparticle-aptamer hybrids, have identified brain-penetrating aptamers and enhanced the brain delivery efficiency. This review highlights the potential of aptamers to transform CNS-targeted therapies.

The interaction of vanadium compounds of pharmaceutical interest with metal-transport proteins like human serum transferrin (hTF) is poorly understood. Direct structural evidence identifying vanadium binding sites on hTF is still lacking. Here, the X-ray structure of the adduct formed when the potential drug [VIVO(acac)2], with acac = acetylacetonato, reacts with human serum transferrin with Fe3+ bound at the C-lobe only (FeC-hTF) has been solved and compared with new structures of FeC-hTF used as controls. Structural analysis revealed the presence of a [VV2O6]2- anion that can be described as a divanadate(V) anion, [VV2O7]4-, that has one oxygen replaced by the phenolate oxygen of Tyr188. The two vanadium centers adopt tetrahedral geometry, consistent with VV behavior. The binding does not alter the overall conformation of FeC-hTF that retains the open conformation of the N-lobe and the closed conformation of the C-lobe, remaining able to be recognized by the transferrin receptor.

<p>Ferroptosis is an iron‑dependent form of cell death associated with liver pathologies. However, its role in chronic cholestasis remains to be fully elucidated. The present study therefore investigated the pathological mechanism of ferroptosis in a rat model of α‑naphthyl isothiocyanate (ANIT)‑induced chronic cholestasis and evaluated the therapeutic potential of the iron chelator deferoxamine (DFO). Wistar rats were used to establish a chronic cholestasis model via ANIT administration, with a subset of animals receiving DFO treatment. Wistar rats that were subjected to chronic ANIT exposure were found to develop severe liver injury, characterized by impaired function, inflammation and fibrosis. In addition, pronounced iron deposition and hallmark features of ferroptosis, including elevated lipid peroxidation, depleted glutathione, and aberrant expression of acyl‑CoA synthetase long‑chain family member 4 and cyclooxygenase 2, were observed. Ultrastructural analysis revealed distinctive mitochondrial abnormalities consistent with ferroptosis. Mechanistically, these changes appeared to be mediated by suppression of the Kelch‑like ECH‑associated protein 1/nuclear factor erythroid 2‑related factor 2/heme oxygenase 1 antioxidant pathway and dysregulation of key iron metabolism proteins, including transferrin receptor 1 and ferroportin 1. Intervention with DFO markedly ameliorated the cholestatic injury, reduced iron overload and lipid peroxidation, mitigated mitochondrial damage, and normalized the expression of key proteins involved in ferroptosis, antioxidant defense and iron homeostasis. Taken together, these findings suggested that ferroptosis may be a key pathological mechanism in chronic cholestasis, driven by the concurrent disruption of antioxidant and iron metabolic capacities in hepatocytes. Therefore, targeting iron overload may be a promising therapeutic strategy for cholestasis.</p>.

Gynostemma pentaphyllum (GP) is known as the "elixir of life" in Guizhou Province, China, as it has been widely consumed by the elderly. Numerous studies have shown that gypenosides (GPS) extracted from GP are involved in lipid metabolism. Apolipoprotein E (ApoE) is a polymorphic protein with multiple biological functions, such as regulating lipid transport and iron metabolism. The deficiency of ApoE can lead to disorders in both lipid and iron metabolism. Therefore, ApoE knockout (ApoE-/-) mice are widely used in the research of disease models related to lipid and iron metabolism. It has been found through research that GPS ameliorates ApoE deficiency-induced dyslipidemia, while our prior research has established ApoE as indispensable for maintaining systemic iron homeostasis. According to the pharmacological effects of GPS, they can regulate lipid metabolism through pathways such as anti-inflammation and oxidative stress. These pathways also play a crucial role in the body's iron metabolism. Thus, this paper hypothesizes that GPS can reverse the abnormal iron metabolism caused by ApoE deficiency. It further explores the impact of GPS on iron metabolism and the underlying mechanism, aiming to provide a theoretical basis for the development of drugs that regulate iron homeostasis. We randomly divided C57BL/6 mice were randomly divided into blank group (WT), apolipoprotein E knockout group (ApoE KO/ApoE-/-) and gypenosides group (ApoE-/- + GPS). The serum iron content, tissue iron content, transferrin receptor 1 (TfR1), ferroportin 1 (Fpn1), divalent metal transporter 1 (DMT1), iron regulatory proteins (IRPs), ferritin light chain (FTL), ferritin heavy chain (FTH), nuclear factor erythroid 2-related factor 2 (NRF2) and hepcidin expression in liver and spleen of the three groups of mice were studied. The results demonstrate that gypenosides reduce ApoE deficiency-induced iron accumulation by downregulating TfR1 (a cellular iron import protein) and upregulating Fpn1 (an iron export protein). In the spleen of ApoE-/- mice, this regulation occurs through Nrf2-dependent upregulation of Fpn1 and IRP2-mediated downregulation of TfR1, whereas in the liver, neither Nrf2 nor IRPs play a dominant role in the altered expression of TfR1 and Fpn1 induced by ApoE knockout. Gypenosides can reduce tissue iron accumulation in the liver and spleen of ApoE-deficient mice, suggesting that, based on its function in regulating lipid metabolism, gypenosides also possess the potential ability to regulate iron metabolism.

Acute liver injury (ALI) is a potentially life-threatening condition lacking effective clinical drugs. Hypoxia-inducible factor-1α (HIF-1α) is a key regulator of both inflammation and metabolism. In ALI, HIF-1α expressions are upregulated, but the role of HIF-1α in hepatocytes and whether it can be targeted remain unclear. Herein, clinical samples and ALI murine models including lipopolysaccharide/D-galactosamine (LPS/D-GalN), acetaminophen (APAP), and thioacetamide (TAA) revealed an increase in HIF-1α expression and ferroptosis. Using HIF-1α gain and loss of function mouse and hepatocyte culture models, we demonstrated that HIF-1α upregulation exacerbated liver ferroptosis and injury. Mechanistically, HIF-1α/transferrin receptor protein 1 (TFR1) axis drives hepatic iron overload, promoting ferroptotic cell death and liver injury. In addition, TFR1 inhibition reversed HIF-1α-induced ALI. Importantly, pharmacological inhibition of HIF-1α and TFR1 significantly reduced ferroptosis and mitigated liver injury both in vivo and in vitro. Together, our findings demonstrate the pathological role of hepatic HIF-1α, which may serve as a promising target of therapeutic intervention.

Cardiovascular disease is the leading cause of death worldwide, accounting for about a third of all deaths. Traditional risk factors like hypertension, diabetes, dyslipidemia, and obesity are well known, but iron also plays a crucial role in heart health. Iron is essential for oxygen transport, mitochondrial function, and heart muscle activity, and both deficiency and overload can harm cardiovascular outcomes. This review examines studies on iron metabolism, regulation via the hepcidin-ferroportin pathway, myocardial energy, oxidative stress, and clinical trials of iron supplementation or reduction in heart failure, chronic kidney disease, the elderly, women, and athletes. Iron deficiency affects over 60% of heart failure patients, leading to reduced energy, lower exercise capacity, and higher morbidity. Intravenous iron improves functional capacity, quality of life, and reduces hospitalizations, especially in patients with low transferrin saturation. Iron overload, on the other hand, increases oxidative stress, arrhythmias, and cardiomyopathy. Evidence shows a U-shaped relationship between iron and cardiovascular outcomes, emphasizing the importance of markers like transferrin saturation, soluble transferrin receptor, and hepcidin. Iron imbalance contributes to cardiovascular disease. Targeted assessment and treatment, including supplementation for deficiency and chelation or phlebotomy for overload, may improve outcomes. The ultimate aim of this review is to enhance perioperative management and long-term results for this highly vulnerable population by synthesizing current insights and addressing knowledge gaps.

Background/Objectives: Docetaxel is a widely used chemotherapeutic agent for several malignancies and is an established treatment for castration-resistant prostate cancer. However, its poor aqueous solubility, systemic toxicity, and the emergence of drug resistance limit its clinical benefit. Zein, a prolamin, forms micelles that enhance the solubility and delivery of hydrophobic drugs. As PEG length and ligand presentation govern micelle behavior, we investigated transferrin-functionalized PEGylated zein micelles as docetaxel nanocarriers and examined how PEG chain length (5 K vs. 10 K) and transferrin-mediated targeting affect delivery to prostate cancer cells. Methods: Docetaxel-loaded zein micelles bearing 5 K or 10 K PEG chains were prepared and conjugated to transferrin. Formulations were characterized for size, charge, morphology, critical micelle concentration, colloidal stability, drug loading and transferrin density. Cellular uptake and mechanisms were assessed in PC-3-Luc, DU145 and LNCaP cells by confocal microscopy, flow cytometry and pharmacological inhibition. Anti-proliferative activity was determined by MTT assays. Results: Both PEG5K and PEG10K micelles formed micellar dispersions with low polydispersity and high encapsulation efficiency. PEG5K micelles achieved higher transferrin conjugation and drug loading. Transferrin-functionalized PEG5K micelles showed enhanced uptake in DU145 and LNCaP cells but lower internalization in PC-3-Luc cells. Inhibitor studies indicated receptor-dependent uptake via clathrin- and caveolae-mediated endocytosis. Free docetaxel remained the most potent. However, among nanocarriers, transferrin-targeted PEG5K micelles showed the greatest anti-proliferative efficacy relative to their non-targeted counterparts, whereas transferrin-targeted PEG10K micelles were less potent than the non-targeted PEG10K micelles across all three cell lines. Conclusions: PEG chain length and ligand presentation are key determinants of uptake and cytotoxicity of docetaxel-loaded zein micelles. Shorter PEG chains favor effective transferrin display and receptor engagement, whereas longer PEG likely induces steric hindrance and reduces targeting, supporting transferrin-conjugated PEG5K zein micelles (the lead formulation in this study) as a targeted delivery platform that improves performance relative to matched non-targeted micelles in vitro, while free docetaxel remains more potent in 2D monolayer assays.

Transferrin receptor (TfR)-targeting of biologics has emerged as a promising strategy to improve drug delivery across the blood-brain barrier (BBB). However, most preclinical studies evaluating TfR-enabled drugs have been conducted in young adult animals. It remains unclear whether age and aging-related diseases impact TfR protein levels and/or BBB transport capacity. Here, we utilized a previously described TfR-targeting antibody transport vehicle (ATVTfR) to investigate how healthy aging and disease progression in the 5xFAD mouse model of Alzheimer's disease (AD) impact TfR protein and TfR-mediated brain delivery. ATVTfR transport capacity remained stable across 3- to 24-month-old healthy mice and 5xFAD progression did not impair ATVTfR brain transport up to 10.5 months, despite significant amyloid burden. Interestingly, neonates exhibited significantly elevated levels of vascular TfR protein and ATVTfR brain exposure compared to adult mice. Furthermore, vascular TfR in AD patient brains was similar to age-matched controls, suggesting conserved TfR transport is also likely in human AD. Overall, our data demonstrates broad functional utility for TfR-based brain delivery in both healthy aging and in an AD mouse model. Additionally, elevated TfR-mediated brain delivery during early mouse development highlights the potential of added efficacy in utilizing such platforms in disease treatment of infants and children.