Citations

Lipid nanoparticles (LNPs) have evolved into a significant delivery technology for nucleic acid therapies, including messenger RNA (mRNA), small interfering RNA (siRNA), and genome editing tools. Although LNPs have demonstrated therapeutic success, they display strong tropism to the liver when systemically delivered, thus restricting their use for targeted delivery to extrahepatic organs. The major factor responsible for the liver targeting of LNPs is the binding of apolipoprotein E (ApoE) to the nanoparticle surface, which enables their recognition by lipoprotein receptors and uptake by liver cells. However, increasing evidence suggests that the tropism of LNPs can be altered by controlling lipid composition, physical and chemical properties, and acquired biological properties. This review discusses the mechanisms responsible for the liver tropism of LNPs as well as recent trends in modulating LNP tropism to extrahepatic organs. How ionizable lipids, helper lipids and sterols, PEG-lipids, LNP properties, and interaction with the protein corona can impact the organ tropism of LNPs as well as approaches for active and endogenous targeting of LNPs for organ- and cell-specific delivery are discussed. The challenges associated with organ- and cell-selective delivery of nucleic acids, such as delivery to functionally specific cell populations, endosomal release, species-specific translation, safety, repeated dosing, and clinical translation, are also described.

Cardiovascular diseases (CVDs) remain the leading cause of death worldwide, yet therapeutic development is limited by experimental models that incompletely recapitulate human physiology, disease heterogeneity, and treatment responses. Emerging human-relevant models, including patient-derived induced pluripotent stem cells, cardiac organoids, engineered tissues, organ-on-chip systems, genome editing, multi-omics, and computational approaches, are improving the ability to investigate cardiovascular disease mechanisms and therapeutic responses. In this review, we critically compare these technologies with respect to physiological relevance, reproducibility, scalability, throughput, and translational potential. We highlight their applications in disease modeling, drug discovery, toxicity assessment, and precision medicine while examining persistent limitations, including cellular immaturity, incomplete vascularization and systemic integration, model variability, and limited clinical validation. We further discuss how integration of bioengineering, genome editing, multi-omics, and computational methods may improve predictive performance. Standardization, interlaboratory validation, regulatory qualification, and prospective benchmarking against human clinical outcomes will be essential for translating these platforms into reliable tools for cardiovascular research and therapeutic development. Collectively, the convergence of stem cell biology, bioengineering, genome editing, multi-omics, and computational approaches is establishing a new generation of human-centered cardiovascular models with the potential to strengthen mechanistic discovery and accelerate the development of more predictive and personalized therapies.

Cancer immunotherapy is a transformative technology allowing for the elimination of malignant cells through immune system stimulation; however, the large-scale clinical application of adoptive cellular therapy technologies is limited due to difficulties in ex vivo immune cell engineering, high costs, and complicated manufacturing process. Recently, in vivo immune cell engineering was discovered as an emerging approach that allows for the genetic reprogramming of immune cells in patients, thus circumventing many problems inherent to traditional cellular therapy technologies. Breakthroughs in targeted drug delivery systems such as cell-penetrating peptides, antibody- and receptor-mediated delivery approaches, lipid nanoparticles (LNPs), polymeric drug carriers, and biomimetic delivery systems allow for the more effective selective delivery of messenger RNA (mRNA), clustered regularly interspaced short palindromic repeats (CRISPR)/Cas gene editing systems, proteins, and other types of cargo to the target immune cells. In vivo immune cell engineering allows for the efficient generation of chimeric antigen receptor T-cells (CAR-T), CAR- natural killer (NK) cells, engineered macrophages, dendritic cells, and other immune cell types; moreover, transient and permanent immune reprogramming is achievable via vivo technologies. The present review discusses the biological barriers limiting immune cell-targeted delivery, including biodistribution, cellular uptake, intracellular transport, and endosomal escape of delivered drugs, and reviews the latest advancements in targeted delivery technologies addressing these obstacles. We also address the latest applications of in vivo immune cell engineering in hematological malignancies and solid tumors, including mRNA therapeutics, CRISPR-based genome editing, and advanced programmable immunotherapy technologies. Furthermore, we discuss unresolved issues related to the specificity of targeting, efficiency of drug delivery, safety of treatment, manufacturing processes, and regulation of in vivo immune engineering technologies and outline future opportunities arising from the integration of nanomedicine, synthetic biology, genome engineering, and artificial intelligence-assisted materials science.

Introduction Recent transcriptome analysis has demonstrated increased expression of Vascular Endothelial Growth Factor receptor-1 (VEGFR-1/FLT1) and in AD brain. Increased expression of VEGFR1 and its ligand VEGFB were associated with a more rapid rate of cognitive decline, providing evidence of a potential link between increased VEGFR-1 expression in AD pathogenesis. In this study, we explored the potential role of VEGFR-1 expression in neurons on AD pathology. Methods To confirm VEGFR1 expression in AD brains, we first performed immunostaining in AD brain sections (AD - Braak stage V-VI, and normal controls - Braak 0-II). And to determine a potential detrimental role of neuronal VEGFR1 expression on AD associated pathologies, we exposed SH-SY5Y human neuroblastoma cells and mouse primary neurons to either hypoxia conditions (1%O 2 ) or 5 μ Aβ1-42 oligomers or fibrils for 24, 28 and 72hrs. Results In this study, we found preferential staining of VEGFR-1 in the neuropil and neuronal cell bodies both in AD and Control hippocampus and increased VEGFR-1 immunoreactivity in dystrophic neuritic processes in the vicinity of Thio-S positive amyloid plaques in AD brains. And treatment of SH-SY5Y human neuroblastoma cell line and mouse primary neurons, with either hypoxia conditions or Aβ1-42 oligomers, resulted in increased VEGFR-1 expression and cleaved caspase 3 activation, leading to neuronal toxicities/cell death. Similarly, treatment with Aβ1-42 fibrils also increased VEGFR-1 and cleaved caspase 3 protein levels in the SH-SY5Y cells whereas treatment with Aβ1-42 monomers had no effect on VEGFR-1 expression. In addition, we show that over-expression of VEGFR-1 intracellular domains in SH-SY5Y cells directly induced neuronal toxicities and importantly, siRNA-mediated knockdown of VEGFR-1 in neurons prevented the hypoxia, Aβ1-42 oligomer and Aβ1-42 fibril-induced toxicities and cell death phenotypes. Treatment with either hypoxia or Aβ1-42 oligomers also reduced expression of cell survival genes including VEGFR-2 and Hippo pathway YAP1 and siRNA-mediated VEGFR-1 knockdown in the neurons normalized expression of both VEGFR-2 and YAP1. Using differential gene expression analysis, we demonstrated upregulation of several inflammatory/interferon-stimulated genes (ISGs) as well as increased expression of genes involved in activation of oxidative stress and cell death pathways in response to Aβ1-42 oligomers treatment in mouse primary neurons. And siRNA-mediated VEGFR-1 knockdown in the mouse primary neurons, reduced gene expression of both the ISGs and oxidative stress/cell death pathways in response to Aβ1-42 oligomer treatment. Discussion In summary, these results show that siRNA-mediated knockdown of VEGFR-1 in neurons significantly prevented hypoxia, Aβ1-42 oligomer and Aβ1-42 fibril-induced cellular toxicities and cell death phenotypes, indicating a potential detrimental role of aberrant VEGFR-1 expression and signaling in response to AD associated pathologies.

With limited therapeutic progress despite aggressive multimodal treatment, glioblastoma (GBM) remains one of the deadliest primary brain tumors. Emerging evidence suggests that GSCs are key drivers of tumor initiation, intratumoral heterogeneity, therapeutic resistance, and recurrence. GSCs retain self-renewal capacity, multilineage differentiation potential, and remarkable plasticity, enabling them to adapt to diverse microenvironmental cues. These properties are upheld by dysregulated developmental and oncogenic signaling pathways, including Notch, Wnt/β-catenin, Hedgehog, PI3K/AKT/mTOR, and STAT3, as well as epigenetic and metabolic reprogramming. In addition, dedicated niches such as hypoxic and perivascular microenvironments critically support GSC maintenance and immune evasion. In this review, we summarize the current understanding of the molecular pathways governing GSC biology, examine their interactions with the tumor microenvironment, and discuss emerging therapeutic strategies targeting GSCs, including pathway inhibition, differentiation therapy, immunotherapy, and nanomedicine-based drug delivery. We highlight key challenges and future directions for translating GSC-targeted approaches into effective clinical interventions for GBM.

Abstract Background Glioblastoma (GBM) is the most common high-grade primary malignant brain tumor, characterized by a notably poor prognosis. Current treatments for GBM have shown limited effectiveness in improving patient survival, highlighting the urgent need for novel therapeutic strategies. Combination therapy offers significant potential in overcoming resistance by targeting multiple signaling pathways; however, it often comes with increased toxicity compared to monotherapy. Co-encapsulating multiple therapeutic agents into a tumor-targeted drug delivery platform holds promise for overcoming these limitations and improving treatment outcomes. Methods We developed a tumor-targeted liposomal nanoformulation (TTL) using phospholipids, cholesterol, DSPE-(PEG)2000-OMe, and a proprietary tumor-targeting peptide (TTP). The TTL was loaded with everolimus (TTL-E), vinorelbine (TTL-V), rapamycin (TTL-R), a combination (TTL-EV), or (TTL-RV). These formulations were tested in vivo on orthotopic GBM mice, combined with temozolomide and radiation. RNA sequencing was performed to identify molecular and transcriptome changes post-treatment. Results TTL demonstrated tumor-specific uptake, effectively delivering drugs to GBM tumors. TTL-EV and TTL-RV outperformed single-drug formulations. Radiation combined with TTL-EV/RV improved tumor growth inhibition and survival, while temozolomide provided minimal benefit. Transcriptome analysis revealed differentially expressed genes (DEGs) linked to DNA damage repair, cell cycle, metabolism, and extracellular matrix pathways. Conclusion TTL crossed the blood-brain barrier, targeting tumors effectively. Radiation plus TTL-EV/RV enhanced tumor suppression and survival in GBM models. Gene expression analysis identified DEGs related to DNA damage and cell death. Mechanistic studies suggest TTL-EV plus radiation inhibits mTOR/MAPK pathways and sensitizes tumors to radiation. These findings offer a potential approach for improving GBM treatment.

Myocardial infarction (MI) remains a leading cause of mortality worldwide, yet effective cardioprotective strategies remain limited in clinical settings. Vascular endothelial growth factor B (VEGFB) has emerged as a promising therapeutic candidate in MI, but the role of its co-receptor, Neuropilin-1 (NRP1), in cardiomyocyte (CM) survival under ischemic stress remains poorly understood. Here, we investigated VEGFB-NRP1 signaling using an in vivo zebrafish model of cardiac injury as well as in vitro hypoxia models in CMs. We demonstrated that VEGFB overexpression conferred protection against ischemic injury and enhanced cardiac regeneration in the zebrafish heart. Mechanistically, we showed that VEGFB treatment enhances CM viability through reducing reactive oxygen species (ROS), ferroptosis activation, and preserving mitochondrial integrity. We also demonstrated that NRP1 knockdown in the CMs abolished the VEGFB-mediated protective effects, indicating the significant role of NRP1 signaling in VEGFB-induced cardioprotective effects in MI. Lastly, using transcriptome analysis, we confirmed that VEGFB induces anti-apoptotic and anti-ferroptosis gene programs in CMs in response to hypoxic stress. Collectively, our findings provide mechanistic insight into cell death activation pathways, including ferroptosis, in response to ischemic stress and further validate the therapeutic potential of VEGFB in promoting CM survival in ischemic heart disease.

Abstract Background Myocardial infarction (MI) remains a leading cause of mortality worldwide. Recent studies suggest a cardioprotective role for vascular endothelial growth factor-B (VEGF-B) in MI. However, the molecular mechanisms of VEGF-B-mediated signaling via its co-receptor Neuropilin-1 (NRP1) in MI are poorly understood. In this study, we investigated the intricate signaling mechanisms involving VEGF-B and NRP1 in cardiomyocytes (CMs) using ischemic injury as a model of MI. And secondly, we further validated the protective role of VEFG-B in ischemic heart disease, shedding light on their roles not only in cardiac function but also in its therapeutic potential. Methods In this study, we utilized both in vitro and in vivo approaches to elucidate the role of VEGF-B and NRP1 signaling in MI and how it manifests a protective role in mitochondrial functions and cardiac regeneration following ischemic injury. We used two different cardiomyocyte cell lines, H9c2 (rat ventricular cardiomyocytes) and HL-1 (mouse ventricular cardiomyocytes), and induced hypoxia conditions, using either 1% oxygen or 200µM cobalt chloride (CoCl 2 ) to mimic the myocardial infarction-induced ischemic injury in the heart. In addition, we developed a novel heat shock inducible zebrafish model of a cardiomyocyte-specific VEGF-B overexpression system to further examine the protective role of VEGF-B in vivo . Results Our findings indicate that both VEGF-B and NRP1 are predominantly expressed in heart tissue compared to other tissues, and their expression is altered in response to hypoxia/ischemic injury. Our results demonstrate that VEGF-B treatment prior to hypoxia enhances cardiomyocyte survival, while NRP1 knockdown abolishes this protective effect, highlighting a prominent role of NRP1 signaling in VEGF-B-mediated cardio protection. Furthermore, we found that VEGF-B promotes cardiomyocyte survival by improving mitochondrial function, as evidenced by reduced oxidative stress and ROS accumulation, decreased oxidative stress, preserved mitochondrial membrane potential, and increased ATP levels. Lastly, using our VEGF-B transgenic zebrafish model, we demonstrated that VEGF-B overexpression in zebrafish cardiomyocytes protects the heart from ischemic injury and enhances cardiac regeneration in an NRP1-dependent manner. Conclusion Our study has uncovered an important role of VEGF-B-NRP1 signaling axis in VEGF-B mediated cell survival and in beneficial mitochondrial functions in the CMs. Importantly, we also demonstrated that VEGF-B is protective against ischemic injury in vivo using a novel zebrafish model Novelty and Significance What Is Known? Myocardial infarction (MI) results in mitochondrial dysfunction, cardiomyocyte death, and adverse ventricular remodeling. Vascular Endothelial Growth Factor B (VEGF-B) is traditionally associated with cardiac metabolism, survival, vascular biology, particularly in angiogenesis and lipid metabolism. The neurophilin-1 (NRP1) receptor, a co-receptor for VEGF-B, is expressed in cardiomyocytes and implicated in mitochondrial signaling pathways. Emerging evidence suggests that VEGF-B may influence mitochondrial integrity and function under stress conditions. What New Information Does This Article Contribute? VEGF-B exerts a protective effect on cardiomyocyte mitocondria following ischemic injury by preserving mitochondrial function and reducing oxidative stress. NRP1 receptor as a key mediator of VEGF-B modulates mitochondrial homeostasis in cardiomyocytes. VEGF-B signaling can attenuate apoptosis and enhance mitochondrial bioenergetics post-MI, suggesting a novel cardioprotective mechanism. Clinical Implication: These findings suggest that therapeutic strategies aimed at enhancing VEGF-B/NRP1 signaling may improve mitochondrial function and cardiac recovery after MI, offering a novel avenue for limiting heart failure progression in ischemic heart disease.