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.

In recent years, lipid nanoparticles (LNPs) have shown great promise as highly flexible delivery systems for cancer vaccines, which enable effective cargo delivery and allow for controlling their distribution, cell-targeting ability and immunogenicity. Innovations in ionizable lipid chemistry, biodegradable formulations, RNA engineering and LNP design resulted in improvements in RNA encapsulation, endosomal escape, delivery outside the liver, and targeting of lymphoid organs and antigen-presenting cells. All these achievements led to an expansion of strategies for developing cancer vaccines from using only mRNA to personal neoantigen vaccines, self-amplifying RNA (saRNA), circular RNA (circRNA), peptide/protein vaccines, and multi-purpose platforms that combine antigen delivery and modulation of the immune system. LNPs are also studied as tools for altering the tumor microenvironment (TME) and boosting anti-tumor immunity through local delivery of cytokines and innate immune modulators. Preliminary clinical results with personalized mRNA neoantigen vaccines show strong potential for this approach. However, inflammatory toxicity, suitability for repeated dosing, off-target delivery, difficulties with large-scale production, formulation stability, personalized production schedule and regulatory issues are still significant challenges. New biodegradable and PEG-free formulations, innovations in manufacturing and lyophilization technology, and AI-based approaches in lipid screening could help overcome some of these problems.

Background & Aims: We examined treatment patterns and clinical outcomes in a contemporary cohort of children with newly diagnosed inflammatory bowel disease (IBD) in a large, commercially insured U.S. population. Methods: Using the OptumLabs® Data Warehouse, we created an inception cohort of physician-diagnosed IBD in children aged 6–17 years between 2007–23. We examined cumulative incidence of hospitalization, surgery, safety events, and medication use in patients with Crohn's disease (CD) and ulcerative colitis (UC), overall and stratified by diagnostic era, race and ethnicity, sex, and age at diagnosis. Results: Among 787 children with newly diagnosed CD (age at diagnosis, 13.4±2.9y; 57% male; 82% White, 5% Black, 7% Hispanic) followed over mean 4.6±3.0y, 5-year risk of IBD-related hospitalization and major surgery was 30% and 10%, respectively. In children diagnosed in 2019–23, 1-year cumulative use of corticosteroids and advanced therapy was 46% and 75%, respectively; advanced therapy use increased significantly over time (aHR, 3.43 [95% CI, 2.71–4.32] for 2019–23 vs. 2007–12), while corticosteroid use declined (0.67 [0.53–0.84]). Risk of IBD-related hospitalization was lower in children diagnosed between 2019–23 (0.65 [0.43–0.97]) compared with those diagnosed between 2007-12; surgical risk did not decline significantly, with confidence intervals compatible with a clinically meaningful reduction. Among 399 children with newly diagnosed UC (age at diagnosis, 14.0±3.0y; 53% male; 78% White, 5% Black, 7% Hispanic) followed over 4.5±3.0y, 5-year risk of IBD-related hospitalization and colectomy was 36% and 8%, respectively. Advanced therapy use increased significantly over time (4.46 [2.85–6.98] for 2019–23 vs. 2007–12), with no significant change in hospitalization or surgical risk across eras. No consistent racial and ethnic, age, or sex differences in advanced therapy use or clinical outcomes were identified in either CD or UC. Conclusions: In a contemporary cohort of commercially insured children with newly diagnosed IBD, early advanced therapy use has increased markedly over time. Surgical risk did not decline significantly in either disease; however, the study was not powered to exclude a clinically meaningful reduction, and these findings are hypothesis-generating rather than conclusive.

Background African American adults experience a disproportionate burden of dementia, shaped by structural and clinical factors that remain unclear. Objective To quantify associations between multimorbidity, polypharmacy, and cognition in the context of neighborhood disadvantage. Methods This study is a cross-sectional analysis of 348 African American adults aged 45–92 years (mean 64.3 years; 73.6% female) from the Aging Research Characterizing Health Exposome via Social drivers (ARCHES) cohort. Comorbidity burden was assessed using a modified Charlson Comorbidity Index (CCI), polypharmacy as ≥5 medications, and neighborhood disadvantage using the Area Deprivation Index (ADI). Linear regression estimated associations with a Preclinical Alzheimer’s Cognitive Composite (PACC). The polypharmacy model included modified CCI as a covariate, and effect modification by ADI was assessed using an interaction term between polypharmacy and ADI. Results Higher modified CCI was associated with lower cognitive performance (B = −0.071; 95% CI: −0.130, −0.012). Polypharmacy was not independently associated with cognition after modified CCI adjustment (B = −0.081; β = −0.057; p = 0.257). No significant ADI interaction was found (p = 0.064).

Background/Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as a promising therapeutic option for women with polycystic ovary syndrome (PCOS). Clinical trials and data demonstrate significant improvements in body weight, insulin resistance, hyperandrogenism, and, in some studies, menstrual regularity and reproductive outcomes. However, the current evidence base remains disproportionately focused on short-term metabolic and anthropometric endpoints, while outcomes most relevant to patients—including treatment satisfaction, gastrointestinal tolerability, psychological well-being, body image, fertility planning, financial burden, and long-term adherence—remain inadequately characterized. Methods: We searched PubMed and Google Scholar for English-language literature published between 2021 and 2026, using structured keyword searches. This narrative review evaluates the literature on GLP-1RA use in PCOS beyond weight-focused outcomes, examining mechanisms of action, comparative tolerability across agents, and patient-centered domains including quality of life, eating behavior, and reproductive planning. Results: The published literature reveals a substantial gap between trial-reported completion rates and treatment success, and actual persistence and patient satisfaction. This discrepancy is particularly consequential in PCOS, where treatment decisions intersect with high baseline rates of depression, anxiety, and body image disturbance, and where ovulatory benefits must be weighed against mandatory discontinuation before conception. Conclusions: We identify a systematic absence of validated patient-reported outcome measures, standardized core outcome sets, and long-term follow-up data after treatment withdrawal. This review proposes a research agenda prioritizing patient-centered endpoints as co-primary outcomes, structured assessment of acceptability and persistence, qualitative and mixed-methods approaches, and a dedicated study of fertility planning and treatment interruption.

Abstract Objective This study was conducted to review and synthesize current evidence on anti‐calcitonin gene‐related peptide (CGRP) therapies in women with menstrual‐related migraine, during pregnancy and lactation, and while using hormonal contraception. Background Migraine disproportionately affects women, with prevalence peaking during reproductive years when hormonal fluctuations modulate neurovascular and nociceptive pathways, including CGRP signaling, that contribute to migraine susceptibility. Despite the established efficacy of anti‐CGRP therapies—including monoclonal antibodies (erenumab, fremanezumab, galcanezumab, and eptinezumab) and gepants (ubrogepant, rimegepant, atogepant, and zavegepant)—evidence regarding their use across critical reproductive health contexts remains limited. Methods A systematic search of MEDLINE and Embase was conducted using MeSH terms and keywords related to migraine, CGRP‐targeted therapies, and reproductive health contexts. Studies were screened independently by two reviewers. Data were extracted using standardized forms and synthesized narratively by clinical domain. Results Sixteen studies met inclusion criteria. For menstrual‐related migraine, post hoc analyses and observational studies demonstrate that CGRP monoclonal antibodies reduce migraine frequency both during and outside the perimenstrual window (galcanezumab: −5.1 vs. −3.2 days, p < 0.001), although the perimenstrual period remains a time of relatively higher headache burden despite treatment. Pregnancy data are limited to pharmacovigilance analyses and case reports of unintended exposures, which have not identified specific patterns of maternal, fetal, or neonatal toxicity. Phase 1 pharmacokinetic studies demonstrate minimal gepant transfer into breast milk (relative infant doses, 0.04%–0.19%), well below the 10% safety threshold, although no human lactation data exist for CGRP monoclonal antibodies. No studies specifically evaluated anti‐CGRP therapies in women using hormonal contraceptives. Conclusion Substantial evidence gaps exist across all reproductive health contexts examined. Prospective trials in menstrual‐related migraine, pregnancy registries, lactation studies assessing infant outcomes, and research examining interactions with hormonal contraceptives are needed to optimize migraine care for women.

Introduction Extracranial internal carotid artery (ICA) aneurysms are rare (<1% of arterial aneurysms) yet clinically significant due to risks of distal embolization, local compressive symptoms, and, less commonly, rupture. High-quality evidence is limited, and no consensus guidelines exist, management is therefore individualized to aneurysm morphology, cervical segment involvement, vessel tortuosity, and operator expertise. Flow diversion with Pipeline Embolization Device (PED) achieves aneurysm exclusion while reconstructing the parent artery and is especially useful in tortuous cervical segments. Clinical Summary A 60-year-old woman with incidentally discovered bilateral cervical ICA aneurysms (left 2.3 cm mid-ICA; right 0.5 cm) and a type III bovine arch underwent PED diversion of the lesion. Via femoral access, a long 6-F Fubuki sheath (Asahi Intecc, Irvine, USA) with Sofia catheter (Micro-Vention, Tustin, USA) support and systemic heparinization (ACT >250 s) enabled deployment of a 5.0 × 25 mm Pipeline Flex (Medtronic Neurovascular, Irvine, USA) across the aneurysm neck. Immediate angiography showed intra-aneurysmal stasis while preserving parent-artery flow . At 12 months, she is asymptomatic with a 70% reduction in the contrast-opacified aneurysm component to 7 mm, and the contralateral small aneurysm remains stable. Conclusion Flow diversion with a PED provided an effective, artery-preserving solution for a mid-cervical ICA aneurysm in tortuous anatomy, achieving immediate flow stasis with parent-artery patency. At 12 months, the patient is asymptomatic with a contrast-opacified component reduced to 7 mm. This case supports using flow diversion for extracranial ICA aneurysms when anatomy is favorable, alongside careful antiplatelet therapy and planned imaging follow-up.

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.

Abstract Context. Thyroid nodule ultrasound findings are crucial in guiding management decisions for patients with thyroid nodules. However, the frequency with which ultrasound images are discussed and reviewed with patients during clinical visits is not well understood. Objective. To assess how often thyroid ultrasound images are shown and discussed with patients during consultations, and to identify predictors of image review during clinical visits. Design and setting. Secondary analysis of a multicenter pilot randomized clinical trial conducted at two academic medical centers in the United States. Participants. Adults undergoing evaluation for thyroid nodules. Intervention. Participants were randomized to receive either usual care or care enhanced with a conversation aid. Main Outcome Measures. The primary outcome was the frequency of thyroid nodule imaging review evaluated as a binary outcome. Secondary outcomes included evaluation of predictors of image discussion. Results. Eighty-five patients were evaluated. Most participants were women (80%), mean age (60 years, SD 16), and White (86%), undergoing new patient visits (84%). Thyroid nodule ultrasound images were reviewed with patients in 53% of visits (45/85), and in all cases, clinicians initiated the imaging discussion. Predictors of image review included type of consultation (new patient visit) (OR 10.6, 95% CI: 1.79, 62.3). Age, sex, study arm, thyroid nodule size or cancer risk and plan of care (e.g., completing a biopsy) were not statistically associated with review of clinical images. Conclusions. Review of thyroid ultrasound images during clinical visits is relatively common, with consultation type serving as significant predictor.

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.