Biology subjects

Chung, E. J.

Publications and source records attributed to Chung, E. J..

6 recordsLinked to original sources

bioRxiv2026

Combination siRNA delivery as a therapeutic strategy for ADPKD

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease worldwide, characterized by progressive cyst growth and inflammation, yet effective targeted therapies remain limited. Here we show that TMEM16A and MCP-1, key mediators of cyst-lining epithelial expansion and inflammatory macrophage recruitment respectively, are consistently upregulated in cyst-lining collecting duct (CD) epithelia across murine, porcine, and human ADPKD models. In human ADPKD patient cells, although individual silencing of TMEM16A or MCP-1 transcripts reduced cyst growth, combined silencing produced superior therapeutic efficacy, establishing the rationale for evaluating dual-target delivery. To achieve dual gene silencing in the kidneys, we delivered Tmem16a and Mcp-1 siRNA using peptide amphiphile micelles (PAMs), an ultrasmall nanoparticle platform that enables efficient renal targeting. To redirect siRNA-loaded PAMs to CD epithelia, we functionalized their surface with a CD-targeting peptide (CDM), which enabled preferential accumulation in cyst-lining CD epithelia. In an inducible Pkd1-deficient mouse model, co-delivery of CDMs loaded with Tmem16a and Mcp-1 siRNA reduced kidney enlargement, cystic burden, tubular injury, and macrophage infiltration, with efficacy exceeding non-targeted siRNA delivery at equivalent doses. CDM demonstrated enhanced uptake in primary human ADPKD patient-derived CD cells and dual gene silencing reduced target gene expression and cyst expansion, establishing translational relevance. These findings establish CD peptide-functionalized micelles as a route to cell-type-selective RNAi in the kidney, delivering siRNA to cyst-lining CD cells. Furthermore, because both targets, TMEM16A and MCP-1, are transcribed within CD cells, our siRNA-loaded CD-targeting micelles silence two drivers of cyst expansion, and their simultaneous suppression represents an effective therapeutic strategy for ADPKD.

bioengineering↗

bioRxiv2026

Collecting Duct-Targeted Lipid Nanoparticles Deliver Pkd2 mRNA to Restore Polycystin-2 and Attenuate ADPKD

Autosomal dominant polycystic kidney disease (ADPKD), a leading genetic cause of kidney failure, is caused by mutations in the PKD1 or PKD2 genes, resulting in functional polycystin 1 (PC1) or polycystin 2 (PC2) deficiency, and is characterized by progressive cyst expansion in the kidneys. However, no approved therapy directly restores polycystin expression, and current treatments target downstream pathways rather than the genetic defect. Gene replacement therapy offers a direct route to functional rescue, but efficient delivery to cyst-lining renal epithelia remains a major barrier. To meet this challenge, we developed a lipid nanoparticle (LNP) that incorporates a collecting duct (CD) targeting peptide (CD LNPs) to enable delivery of Pkd2 mRNA (CD-mPkd2) to renal CD epithelia, the predominant site of cyst origin. CD LNPs increased renal accumulation and targeted CD cells in vivo, outperforming non-targeted formulations. In a Pkd2-deficient mouse model, repeated administration of CD-mPkd2 induced reversal of established cystic disease, restored renal architecture, and reduced the fibrotic and inflammatory microenvironment characteristic of ADPKD. Furthermore, CD-mPkd2 was well tolerated without detectable off-target toxicity. Given that PC2 supplementation can attenuate disease in Pkd1-deficient models, we further demonstrate that a single dose of CD-mPkd2 reduces cyst burden and improves renal function across this distinct genetic background. These findings establish CD-mPkd2 as a potential therapeutic strategy for ADPKD across genetic backgrounds.

bioengineering↗

bioRxiv2026

Ablation of glypican-3 enhances radiosensitivity in liver cancer by prolonging G2/M arrest and activating the ATM/CHK2 pathway

Glypican-3 (GPC3) is an oncofetal protein widely being explored as a diagnostic and therapeutic target in hepatocellular carcinoma (HCC). Given that radiotherapy in the form of external beam and radioembolization are standard-of-care treatments for HCC, we aimed to determine whether there was any relationship between GPC3 and response to radiotherapy. Here, we demonstrate that GPC3 expression confers radioresistance in liver cancer through integrated in vitro, in vivo, and patient-level clinical analyses. Stable GPC3-knockout in liver cancer cell lines (HepG2, Hep3B, Huh7) and ectopic GPC3 expression in GPC3-negative liver cancer cells (SNU449), as well as in non-hepatic A431 cells, demonstrated that GPC3-mediated radioresistance is not restricted to hepatic lineage. Following irradiation, GPC3-deficient cells exhibited reduced proliferation, impaired clonogenic survival, persistent DNA damage, prolonged G2/M arrest, and increased apoptosis. Transcriptomic profiling demonstrated enrichment of cell-cycle and DNA damage response pathways in irradiated GPC3-deficient cells compared with GPC3-positive cells, and protein analyses confirmed sustained activation of the ATM/CHK2 axis. In vivo, GPC3 deletion markedly enhanced radiation-induced tumor growth delay in both HepG2 and A431 xenograft models. Consistent with these findings, high GPC3 expression was associated with inferior clinical outcomes in patients with HCC undergoing external-beam radiotherapy or radioembolization. Together, these findings identify GPC3 as a determinant of radioresistance in liver cancer and suggest its potential utility as a biomarker to guide radiotherapeutic strategies. Significance statementRadiotherapy is an important treatment option for HCC, but biomarkers that predict tumor response remain limited. GPC3 is highly expressed in most HCCs and is being investigated as an important biomarker for diagnosis and treatment of this disease, yet its relationship, if any, on radiosensitivity has not been previously reported. Here, we identify GPC3 as a modulator of radioresistance. GPC3 loss enhances radiosensitivity and is associated with persistent unresolved DNA damage, prolonged G2/M arrest, and sustained activation of the ATM/CHK2 pathway, resulting in delayed tumor growth after irradiation. In a clinical cohort of patients treated with radiotherapy, high GPC3 expression was associated with poorer overall survival. These findings suggest that GPC3 expressing tumors may necessitate either more dose-intense radiotherapy, radiobioligically ablative and/or combined with other modalities, or alternative therapeutic modalities to adequately treat HCC.

cancer biology↗

bioRxiv2022

Oral Delivery of Kidney Targeting Nanotherapeutics for Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disorder. Although a variety of candidate drugs have been found to modulate cystogenesis in animal studies, results from clinical trials have often been unfavorable due to low renal bioavailability and drug-induced side effects. To mitigate this, nanoparticles can be designed to deliver drugs directly to the target organ to increase effective dose while limiting off-target side effects. Unfortunately, there are no kidney-targeted nanomedicines clinically available, and most of the existing FDA-approved nanoparticles require intravenous administration which is not suitable for ADPKD that require lifelong therapy. To address this, we developed an oral drug delivery system using chitosan nanoparticles (CS-NP) that were loaded with peptide amphiphile micelles carrying metformin (met), an ADPKD drug candidate (CS-KM-met). We previously showed that CS-NP can shield met in the gastrointestinal tract; thus, we hypothesized that CS-NP could also enhance bioavailability of kidney-targeting micelles (KMs) upon oral administration. Specifically, we measured the loading capacity of KM-met in CS-NP, evaluated the stability of CS-KM-met under acidic conditions that mimic the gastric environment, and measured in vitro therapeutic effects. Upon oral administration in C57BL/6J mice, CS-KM-met showed significantly greater bioavailability and accumulation in the kidneys as compared to KM-met without CS-NP or free met for up to 24 hours. As such, CS-KM-met showed enhanced therapeutic efficacy in vivo upon oral administration in PKD mice (Pkd1fl/fl; Pax8-rtTA; Tet-O-Cre) compared to KM-met only. Herein, we demonstrate the potential of an oral delivery nanoformulation for the treatment of chronic kidney diseases such as ADPKD for the first time.

bioengineering↗

bioRxiv2022

Unusual Morphological Changes of Rugositalea oryzae, A Novel Wrinkled Bacterium Isolated from The Rice Rhizosphere, Under Nutrient Stress

Bacterial cell morphology might result from natural selection to gain a competitive advantage under environmentally stressful conditions such as nutrient limitation. A bacterial strain YC6860T isolated from the rhizosphere of rice (Oryza sativa L.) showed pleomorphic behavior with smooth cell morphology and wrinkled surface rods depending upon nutritional conditions. Based on scanning and transmission electron microscopy studies, we hypothesized that the surface-to-volume ratio of cells increases with decreasing nutrient concentrations. The transition from smooth to wrinkled cell surface morphology could be one of the adaptation strategies by which YC6860T maximizes its ability to access available nutrients. To characterize the properties of the wrinkled strain, we performed taxonomic and phylogenetic analyses. 16S rRNA gene sequencing results showed that the strain represented a novel, deep-rooting lineage within the order Rhizobiales with the highest similarity of 94.2% to Pseudorhodoplanes sinuspersici RIPI 110T. Whole genome sequencing was also performed to characterize its genetic features. The strain YC6860T might belong to a new genus, named Rugositalea, and a new species, named Rugositalea oryzae, In addition, taxonomic analysis showed that YC6860T is Gram-negative, aerobic, and rod-shaped with large regular wrinkles resembling a delicate twist of fusilli, measuring 0.5-0.6 {micro}m in width and 1.5-1.6 {micro}m in length under nutrient-limiting conditions. This unique cell structure with regular rugosity could be the first finding that has not been reported in the existing bacterial morphology.

microbiology↗

bioRxiv2020

Nanoparticle-mediated microRNA-145 Delivery for Vascular Smooth Muscle Cell Phenotype Modulation and Atherosclerosis Treatment

Vascular smooth muscle cells (VSMCs) change from contractile to the synthetic phenotype during atherogenesis and 30-70% of cells that make up plaques have been elucidated to be of VSMC origin. MicroRNA-145 (miR-145) is responsible for regulating VSMC phenotypic switching, and low miR-145 levels in circulation have been linked with atherosclerosis. Hence, we developed nanoparticles for targeted delivery of miR-145 by synthesizing micelles co-assembled with miR-145 and the CCR2-binding peptides for plaque targeting. The miR cargo was protected in micelles from premature endosomal degradation and rescued contractile markers in synthetic VSMCs and SMCs isolated from patient arteries in vitro. In ApoE-/- mid-stage atherosclerotic mice, miR-145 micelles halted plaque growth and maintained contractile phenotypes similar to baseline levels. In early-stage atherosclerosis, a single dose of miR-145 micelles prevented lesion growth by 49%. We present the potential of miR-145 micelles as a therapeutic that can be applied longitudinally and intervene throughout atherosclerosis pathogenesis.

bioengineering↗