Persistence and enrichment of dominant T cell clonotypes in expanded tumor-infiltrating lymphocytes of breast cancer.

BACKGROUND: Adoptive cell therapy using tumor-infiltrating lymphocytes (TILs) has shown promising results in cancer treatment, including breast cancer. However, clonal dynamics and clinical significance of TIL expansion ex vivo remain poorly understood. METHODS: We investigated T cell receptor (TCR) repertoire changes in expanded TILs from 19 patients with breast cancer. We compared TCR repertoire of TILs at different stages of expansion, including initial (2W TILs) and rapid expansion (REP TILs), and their overlap with formalin fixed paraffin embedded (FFPE) and peripheral blood. Additionally, we examined differences in TCR repertoire between CD4+ and CD8+ REP TILs. RESULTS: In descending order of proportion, average of 60% of the top 10% clonotypes of FFPE was retained in 2W TIL (60% in TRB, 64.7% in TRA). Among the overlapped clonotypes between 2W TILs and REP TILs, 69.9% was placed in top 30% of 2W TIL. The proportion of clonotypes in 2W TIL and REP TIL showed a significant positive correlation. CD4+ and CD8+ T cells show similar results in diversity and CDR3 length. CONCLUSIONS: Our study traces the changes in TILs repertoire from FFPE to 2W TIL and REP TIL and confirmed that clonotypes with high frequencies in TILs have a high likelihood of maintaining their priority throughout culture process.

Expansion of tumor-infiltrating lymphocytes in non-small cell lung cancer: Clinical potential and efficacy in EGFR mutation subsets.

Our study aimed to expand tumor-infiltrating lymphocytes (TILs) from primary non-small cell lung cancers (NSCLCs) and evaluate their reactivity against tumor cells. We expanded TILs from 103 primary NSCLCs using histopathological analysis, flow cytometry, IFN-γ release assays, cell-mediated cytotoxicity assays, and in vivo efficacy tests. TIL expansion was observed in all cases, regardless of EGFR mutation status. There was also an increase in the median CD4+/CD8+ ratio during expansion. In post-rapid expansion protocol (REP) TILs, 13 out of 16 cases, including all three cases with EGFR mutations, exhibited a two-fold or greater increase in IFN-γ secretion. The cytotoxicity assay revealed enhanced tumor cell death in three of the seven cases, two of which had EGFR mutations. In vivo functional testing in a patient-derived xenograft model showed a reduction in tumor volume. The anti-tumor activity of post-REP TILs underscores their potential as a therapeutic option for advanced NSCLC, irrespective of mutation status.

Varus-valgus alignment of humeral short stem in reverse total shoulder arthroplasty: does it really matter?

BACKGROUND: The utilization of short humeral stems in reverse total shoulder arthroplasty has gained attention in recent times. However, concerns regarding the risk of misalignment during implant insertion are associated with their use. METHODS: Eight fresh-frozen cadaveric shoulders were prepared for dissection and biomechanical testing. A bespoke humeral implant was fabricated to facilitate assessment of neutral, varus, and valgus alignments using a single stem, and 10° was established as the maximum permissible angle for misalignments. Shift in humerus position and changes in deltoid length attributable to misalignments relative to the neutral position were evaluated using a Microscribe 3DLx system. The impingement-free range of motion, encompassing abduction, adduction, internal rotation, and external rotation (ER), was gauged using a digital goniometer. The capacity for abduction was evaluated at maximal abduction angles under successive loading on the middle deltoid. A specialized traction system coupled with a force transducer was employed to measure anterior dislocation forces. RESULTS: Relative to the neutral alignment, valgus alignment resulted in a more distal (10.5 ± 2.4 mm) and medial (8.3 ± 2.2 mm) translation of the humeral component, whereas the varus alignment resulted in the humerus shifting more superiorly (11.2 ± 1.3 mm) and laterally (9.9 ± 0.9 mm) at 0° abduction. The valgus alignment exhibited the highest abduction angle than neutral alignment (86.2°, P < .001). Conversely, the varus alignment demonstrated significantly higher adduction (18.4 ± 7.4°, P < .001), internal rotation (68.9 ± 15.0°, P = .014), and ER (45.2 ± 10.5°, P = .002) at 0° abduction compared to the neutral alignments. Anterior dislocation forces were considerably lower (23.8 N) in the varus group compared to the neutral group at 0°ER (P = .047). Additionally, abduction capability was markedly higher in varus alignment at low deltoid loads than the neutral alignment (5N, P = .009; 7.5 N, P = .007). CONCLUSIONS: The varus position enhances rotational range of motion (ROM) but increases instability, while the valgus position does not significantly impact ROM or instability compared to the neutral position.

Targeted nanotherapy for kidney diseases: a comprehensive review.

Kidney diseases represent a major public health problem, affecting millions of people worldwide. Moreover, the treatment of kidney diseases is burdened by the problematic effects of conventional drug delivery, such as systemic drug toxicity, rapid drug clearance, and the absence of precise targeting of the kidney. Although the use of nanotechnology in medicine is in its early stage and lacks robust translational studies, nanomedicines have already shown great promise as novel drug-delivery systems for the treatment of kidney disease. On the basis of our current knowledge of renal anatomy and physiology, pathophysiology of kidney diseases, and physicochemical characteristics of nanoparticles, an expansive repertoire and wide use of nanomedicines could be developed for kidney diseases in the near future. Some limitations have slowed the transition of these agents from preclinical studies to clinical trials, however. In this review, we summarize the current knowledge on renal drug-delivery systems and recent advances in renal cell targeting; we also demonstrate their important potential as future paradigm-shifting therapies for kidney diseases.

Run Your 3D Object Detector on NVIDIA Jetson Platforms:A Benchmark Analysis.

This paper presents a benchmark analysis of NVIDIA Jetson platforms when operating deep learning-based 3D object detection frameworks. Three-dimensional (3D) object detection could be highly beneficial for the autonomous navigation of robotic platforms, such as autonomous vehicles, robots, and drones. Since the function provides one-shot inference that extracts 3D positions with depth information and the heading direction of neighboring objects, robots can generate a reliable path to navigate without collision. To enable the smooth functioning of 3D object detection, several approaches have been developed to build detectors using deep learning for fast and accurate inference. In this paper, we investigate 3D object detectors and analyze their performance on the NVIDIA Jetson series that contain an onboard graphical processing unit (GPU) for deep learning computation. Since robotic platforms often require real-time control to avoid dynamic obstacles, onboard processing with a built-in computer is an emerging trend. The Jetson series satisfies such requirements with a compact board size and suitable computational performance for autonomous navigation. However, a proper benchmark that analyzes the Jetson for a computationally expensive task, such as point cloud processing, has not yet been extensively studied. In order to examine the Jetson series for such expensive tasks, we tested the performance of all commercially available boards (i.e., Nano, TX2, NX, and AGX) with state-of-the-art 3D object detectors. We also evaluated the effect of the TensorRT library to optimize a deep learning model for faster inference and lower resource utilization on the Jetson platforms. We present benchmark results in terms of three metrics, including detection accuracy, frame per second (FPS), and resource usage with power consumption. From the experiments, we observe that all Jetson boards, on average, consume over 80% of GPU resources. Moreover, TensorRT could remarkably increase inference speed (i.e., four times faster) and reduce the central processing unit (CPU) and memory consumption in half. By analyzing such metrics in detail, we establish research foundations on edge device-based 3D object detection for the efficient operation of various robotic applications.

Light-Induced Fluorescence Modulation of Quantum Dot-Crystal Violet Conjugates: Stochastic Off-On-Off Cycles for Multicolor Patterning and Super-Resolution.

Photoswitching or modulation of quantum dots (QDs) can be promising for many fields that include display, memory, and super-resolution imaging. However, such modulations have mostly relied on photomodulations of conjugated molecules in QD vicinity, which typically require high power of high energy photons at UV. We report a visible light-induced facile modulation route for QD-dye conjugates. QD crystal violets conjugates (QD-CVs) were prepared and the crystal violet (CV) molecules on QD quenched the fluorescence efficiently. The fluorescence of QD-CVs showed a single cycle of emission burst as they go through three stages of (i) initially quenched "off" to (ii) photoactivated "on" as the result of chemical change of CVs induced by photoelectrons from QD and (iii) back to photodarkened "off" by radical-associated reactions. Multicolor on-demand photopatterning was demonstrated using QD-CV solid films. QD-CVs were introduced into cells, and excitation with visible light yielded photomodulation from "off" to "on" and "off" by nearly ten fold. Individual photoluminescence dynamics of QD-CVs was investigated using fluorescence correlation spectroscopy and single QD emission analysis, which revealed temporally stochastic photoactivations and photodarkenings. Exploiting the stochastic fluorescence burst of QD-CVs, simultaneous multicolor super-resolution localizations were demonstrated.

Analysis and Development of Antigen-specific T Cells Derived from Peripheral Blood Mononuclear Cells of Healthy Donors.

BACKGROUND/AIM: Adoptive cell therapy using antigen-specific T cells is a promising treatment modality for cancer patients. Various methods to isolate specific T cells and identify corresponding T cell receptor (TCR) sequences are known. This study aimed to identify antigen-specific TCR from T cells isolated using carboxyfluorescein succinimidyl ester (CFSE), which marks proliferating activated T cells. MATERIALS AND METHODS: CFSE stained healthy donor peripheral blood mononuclear cells (PBMCs) were treated with cytomegalovirus (CMV) or Epstein-Barr virus (EBV) peptides for seven days. Then, proliferating T cells with decreased CFSE staining were isolated and single cell VDJ sequencing was performed on isolated T cells to identify antigen-specific TCRs. RESULTS: As antigen-specific TCR candidates, ten TCR clones were selected for the CMV antigen and five for the EBV antigen. The reactivity of ten CMV TCR-transduced T cells and one EBV TCR-transduced T cell toward T2 cells pulsed with CMV or EBV peptide was confirmed via NFAT-luciferase, IFN-γ ELISA, and cytotoxicity assays. CONCLUSION: Identification of antigen-specific TCRs with CFSE staining is a valid method for the development of effective immunotherapy. The identified CMV- or EBV-specific TCRs can be used for adoptive cell therapy to treat cancer.

Theragnostic pH-sensitive gold nanoparticles for the selective surface enhanced Raman scattering and photothermal cancer therapy.

We report a nanoparticle-based probe that can be used for a "turn-on" theragnostic agent for simultaneous Raman imaging/diagnosis and photothermal therapy. The agent consists of a 10 nm spherical gold nanoparticle (NP) with pH-responsive ligands and Raman probes on the surface. They are engineered to exhibit the surface with both positive and negative charges upon mildly acidic conditions, which subsequently results in rapid aggregations of the gold NPs. This aggregation simultaneously provides hot spots for the SERS probe with the enhancement factor reaching 1.3 × 10(4) and shifts the absorption to far-red and near-infrared (which is optimal for deep tissue penetration) by the coupled plasmon resonances; this shift was successfully exploited for low-threshold photothermal therapy. The theragnostic gold NPs are cancer-specific because they aggregate rapidly and accumulate selectively in cancerous cells. As the result, both Raman imaging and photothermal efficacy were turned on under a cancerous local environment. In addition, the relatively small hydrodynamic size can have the potential for better access to targeted delivery in vivo and facilitated excretion after therapy.

Strategy for synthesizing quantum dot-layered double hydroxide nanocomposites and their enhanced photoluminescence and photostability.

Layered double hydroxide-quantum dot (LDH-QD) composites are synthesized via a room temperature LDH formation reaction in the presence of QDs. InP/ZnS (core/shell) QD, a heavy metal free QD, is used as a model constituent. Interactions between QDs (with negative zeta potentials), decorated with dihydrolipoic acids, and inherently positively charged metal hydroxide layers of LDH during the LDH formations are induced to form the LDH-QD composites. The formation of the LDH-QD composites affords significantly enhanced photoluminescence quantum yields and thermal- and photostabilities compared to their QD counterparts. In addition, the fluorescence from the solid LDH-QD composite preserved the initial optical properties of the QD colloid solution without noticeable deteriorations such as red-shift or deep trap emission. Based on their advantageous optical properties, we also demonstrate the pseudo white light emitting diode, down-converted by the LDH-QD composites.

Association of cyclooxygenase-2 expression with endoplasmic reticulum stress and autophagy in triple-negative breast cancer.

Cyclooxygenase-2 plays a role in oncogenesis and its overexpression is associated with triple-negative breast cancer. However, the mechanisms whereby cyclooxygenase-2 contribute to breast cancer are complex and not well understood. Cyclooxygenase-2 overexpression causes hypoxia, oxidative stress, and endoplasmic reticulum stress. The aim of this study is to investigate the correlations among cyclooxygenase-2 expression, endoplasmic reticulum stress-associated molecules, and autophagy-associated molecules in triple-negative breast cancer. Surgical specimens from two cohorts of triple-negative breast cancer patients without neoadjuvant systemic therapy were analyzed: cohorts 1 and 2 consisted of 218 cases from 2004 to 2006 and 221 cases from 2007 to 2009, respectively. Specimens were evaluated by immunohistochemical examination of cyclooxygenase-2, endoplasmic reticulum stress markers, and autophagy markers expression using tissue microarrays. Cyclooxygenase-2 was overexpressed in 29.8% and 23.9% of cases in cohorts 1 and 2, respectively; and it was positively correlated with two out of three endoplasmic reticulum stress-associated molecules (XBP1, p = 0.025 and p = 0.003 in cohort 1 and cohort 2, respectively; PERK, p < 0.001 in both cohorts). Cyclooxygenase-2 was also positively correlated with two out of three autophagy markers (p62, p = 0.002 and p = 0.003 in cohort 1 and cohort 2, respectively; beclin1, p < 0.001 in both cohorts). Although cyclooxygenase-2 was not an independent prognostic factor for distant metastasis free survival and overall survival, its expression was associated with the expression of endoplasmic reticulum stress and autophagy molecules in triple-negative breast cancer.

Clathrin light chain-conjugated drug delivery for cancer.

Targeted drug delivery systems hold the remarkable potential to improve the therapeutic index of anticancer medications markedly. Here, we report a targeted delivery platform for cancer treatment using clathrin light chain (CLC)-conjugated drugs. We conjugated CLC to paclitaxel (PTX) through a glutaric anhydride at high efficiency. Labeled CLCs localized to 4T1 tumors implanted in mice, and conjugation of PTX to CLC enhanced its delivery to these tumors. Treatment of three different mouse models of cancer-melanoma, breast cancer, and lung cancer-with CLC-PTX resulted in significant growth inhibition of both the primary tumor and metastatic lesions, as compared to treatment with free PTX. CLC-PTX treatment caused a marked increase in apoptosis of tumor cells and reduction of tumor angiogenesis. Our data suggested HSP70 as a binding partner for CLC. Our study demonstrates that CLC-based drug-conjugates constitute a novel drug delivery platform that can augment the effects of chemotherapeutics in treating a variety of cancers. Moreover, conjugation of therapeutics with CLC may be used as means by which drugs are delivered specifically to primary tumors and metastatic lesions, thereby prolonging the survival of cancer patients.

Nanotargeted Delivery of Immune Therapeutics in Type 1 Diabetes.

Immune therapeutics holds great promise in the treatment of type 1 diabetes (T1D). Nonetheless, their progress is hampered by limited efficacy, equipoise, or issues of safety. To address this, a novel and specific nanodelivery platform for T1D that targets high endothelial venules (HEVs) presented in the pancreatic lymph nodes (PLNs) and pancreas is developed. Data indicate that the pancreata of nonobese diabetic (NOD) mice and patients with T1D are unique in their expression of newly formed HEVs. Anti-CD3 mAb is encapsulated in poly(lactic-co-glycolic acid)-poly(ethylene glycol) nanoparticles (NPs), the surfaces of which are conjugated with MECA79 mAb that recognizes HEVs. Targeted delivery of these NPs improves accumulation of anti-CD3 mAb in both the PLNs and pancreata of NOD mice. Treatment of hyperglycemic NOD mice with MECA79-anti-CD3-NPs results in significant reversal of T1D compared to those that are untreated, treated with empty NPs, or provided free anti-CD3. This effect is associated with a significant reduction of T effector cell populations in the PLNs and a decreased production of pro-inflammatory cytokine in the mice treated with MECA79-anti-CD3-NPs. In summary, HEV-targeted therapeutics may be used as a means by which immune therapeutics can be delivered to PLNs and pancreata to suppress autoimmune diabetes effectively.

Fluorescence enhancement and end-to-end assembly of bisacridinedione-gold nanorods by calcium ions.

Gold nanorod end-to-end assembly is demonstrated by the selective complexation of a bisacridinedione foldamer with Ca(2+). This setup can be applied as a chemosensor for Ca(2+) ions, as the complex shows selective red-shifting of the nanorod plasmon peak and enhancement in fluorescence from the acridinedione moieties upon exposure to Ca(2+) .

Unique photothermal response and sustained photothermal effect of pH-responsive gold-nanoparticle aggregates.

Hot gold: The photothermal response upon pulsed laser irradiation is studied for pH-responsive gold-nanoparticle aggregates and compared to that of gold nanorods. The aggregates show a slight red shift in the absorption spectrum and retain the photothermal effect, whereas the nanorods lose the photothermal effect and exhibit a stark blue shift in the absorption.

A Study on the Effectiveness of IT Application Education for Older Adults by Interaction Method of Humanoid Robots.

Education using humanoid robots can have a positive impact in many fields, including in medical or physical training. This study investigated the effects of robot interactions with respect to facial expressions, gestures, voices and their combinations on the education of the elderly regarding information and communications technology (ICT) from functional and emotional perspectives. In this study, the robot's interaction methods were divided into four categories: (1) voice, (2) voice and expression, (3) voice and gesture, and (4) voice and expression and gesture. An experiment involving an educational application with a humanoid robot was conducted with a total of 15 elderly people over the age of 60. The effect of the humanoid robot's interaction method on education was identified by means of subjective survey evaluation and practice performance data analysis, including error rate, task success rate, and number of retrainings. Through the experiment, functional and emotional aspects of effects were measured. The results showed that performance and perceived effectiveness were not significantly affected by the type of robot interaction, but the degree to which the robot felt like it had emotions, the degree to which the robot felt like a human, and the degree to which the robot was friendly were significantly different according to the interaction type employed by the humanoid robot. The best effect was achieved when voice and gesture were used together during tutoring. Recognizing that ICT education using humanoid robots increases interest and participation in education, such robots are concluded to be a suitable method for performing ICT education. In addition, when designing robotic interactions, the use of the robot's voice and gestures together is expected to lead to greater anthropomorphism, resulting in a stronger relationship with humanoid robots.

CD38 reduces mitochondrial fitness and cytotoxic T cell response against viral infection in lupus patients by suppressing mitophagy.

Infection is one of the major causes of mortality in patients with systemic lupus erythematosus (SLE). We previously found that CD38, an ectoenzyme that regulates the production of NAD+, is up-regulated in CD8+ T cells of SLE patients and correlates with the risk of infection. Here, we report that CD38 reduces CD8+ T cell function by negatively affecting mitochondrial fitness through the inhibition of multiple steps of mitophagy, a process that is critical for mitochondria quality control. Using a murine lupus model, we found that administration of a CD38 inhibitor in a CD8+ T cell-targeted manner reinvigorated their effector function, reversed the defects in autophagy and mitochondria, and improved viral clearance. We conclude that CD38 represents a target to mitigate infection rates in people with SLE.

Delivery of costimulatory blockade to lymph nodes promotes transplant acceptance in mice.

The lymph node (LN) is the primary site of alloimmunity activation and regulation during transplantation. Here, we investigated how fibroblastic reticular cells (FRCs) facilitate the tolerance induced by anti-CD40L in a murine model of heart transplantation. We found that both the absence of LNs and FRC depletion abrogated the effect of anti-CD40L in prolonging murine heart allograft survival. Depletion of FRCs impaired homing of T cells across the high endothelial venules (HEVs) and promoted formation of alloreactive T cells in the LNs in heart-transplanted mice treated with anti-CD40L. Single-cell RNA sequencing of the LNs showed that anti-CD40L promotes a Madcam1+ FRC subset. FRCs also promoted the formation of regulatory T cells (Tregs) in vitro. Nanoparticles (NPs) containing anti-CD40L were selectively delivered to the LNs by coating them with MECA-79, which binds to peripheral node addressin (PNAd) glycoproteins expressed exclusively by HEVs. Treatment with these MECA-79-anti-CD40L-NPs markedly delayed the onset of heart allograft rejection and increased the presence of Tregs. Finally, combined MECA-79-anti-CD40L-NPs and rapamycin treatment resulted in markedly longer allograft survival than soluble anti-CD40L and rapamycin. These data demonstrate that FRCs are critical to facilitating costimulatory blockade. LN-targeted nanodelivery of anti-CD40L could effectively promote heart allograft acceptance.

Simultaneous targeting of primary tumor, draining lymph node, and distant metastases through high endothelial venule-targeted delivery.

Cancer patients with malignant involvement of tumor-draining lymph nodes (TDLNs) and distant metastases have the poorest prognosis. A drug delivery platform that targets the primary tumor, TDLNs, and metastatic niches simultaneously, remains to be developed. Here, we generated a novel monoclonal antibody (MHA112) against peripheral node addressin (PNAd), a family of glycoproteins expressed on high endothelial venules (HEVs), which are present constitutively in the lymph nodes (LNs) and formed ectopically in the tumor stroma. MHA112 was endocytosed by PNAd-expressing cells, where it passed through the lysosomes. MHA112 conjugated antineoplastic drug Paclitaxel (Taxol) (MHA112-Taxol) delivered Taxol effectively to the HEV-containing tumors, TDLNs, and metastatic lesions. MHA112-Taxol treatment significantly reduced primary tumor size as well as metastatic lesions in a number of mouse and human tumor xenografts tested. These data, for the first time, indicate that human metastatic lesions contain HEVs and provide a platform that permits simultaneous targeted delivery of antineoplastic drugs to the three key sites of primary tumor, TDLNs, and metastases.

A Survey of Koreans on Sleep Habits and Sleeping Symptoms Relating to Pillow Comfort and Support.

The number of people who complain of sleep disturbances is steadily increasing. An understanding of sleep-related factors is required to address sleep problems. This survey study investigated the sleep habits and sleeping symptoms relating to the comfort and support characteristics of pillows and the relationship between sleep quality and pillow design factors. The study utilized data from 332 participating Korean adults aged 20-76 years (mean age ± SD: males, 40.4 ± 15.2; females, 42.9 ± 15.4). We developed a questionnaire that evaluated sleep habits (sleep duration, bedtime, wake-up time and sleeping position); sleeping symptoms (snoring or coughing, breathing and sleepiness during waking hours) based on the Korean version of the Pittsburgh Sleep Quality Index (PSQI-K) questionnaire; and pillow-related factors (support, comfort, fatigue, height and shape) from existing pillow studies. The average sleep duration was 6.8 h, with more than half (52%) of participants sleeping in the supine position. The overall score for sleep quality was considered poor (4.84 points on a seven-point Likert scale), with some degree of sleepiness during waking hours (4.4 points on a seven-point Likert scale). Females went to bed earlier than males and were more likely to sleep in the lateral position compared to males. The number of toss and turn or waking events during sleep increased with age, and older individuals went to sleep earlier and woke up earlier. Among the symptoms of fatigue, pain, discomfort with changing position, snoring, coughing and breathing discomfort, participants reported their highest levels of discomfort due to sleepiness after waking, and they experienced the least head pain. Participants who used a regular-type pillow had poorer satisfaction on multiple comfort and support factors (support, comfort, height suitability, shape suitability) compared with those who used a functional-type pillow. Less head fatigue, less neck fatigue and less shoulder pain had significant effects on sleep quality. To reduce neck fatigue and shoulder pain, designers should consider the height for neck support in the lateral position. To reduce neck fatigue, it is desirable to use materials like latex or memory foam that provide neck support, which can improve sleep quality. The findings of this study contribute to a better understanding of sleep habits and characteristics of pillow comfort and provide practical guidelines for better pillow designs.

Selective Trafficking of Light Chain-Conjugated Nanoparticles to the Kidney and Renal Cell Carcinoma.

Specific delivery platforms for drugs to the kidney and diagnostic agents to renal cell carcinoma (RCC) constitute urgent but unfulfilled clinical needs. To address these challenges, we engineered nanocarriers that interact selectively for the first time with proximal tubule epithelial cells (PTECs) in the kidney and with RCC through the interplay between lambda light chains (LCs) attached to PEGylated polylactic-co-glycolic acid (PLGA) nanoparticles and the membrane protein megalin. Systemic administration of these light chain-conjugated nanoparticles (LC-NPs) to mice resulted in their specific retention by megalin-expressing PTECs for seven days. Repetitive dosing of LC-NPs demonstrated no renal toxicity. LC-NPs also localized selectively to megalin-expressing RCC tumors in mice. Moreover, we confirmed that both the primary tumor and lymph node metastases of human RCC express megalin, reinforcing the potential of LC-NPs for clinical use. Thus, LC-NPs can contribute potentially to improving the management of both non-oncologic and oncologic renal disorders.