Preclinical proof of principle for orally delivered Th17 antagonist miniproteins.

Interleukin (IL)-23 and IL-17 are well-validated therapeutic targets in autoinflammatory diseases. Antibodies targeting IL-23 and IL-17 have shown clinical efficacy but are limited by high costs, safety risks, lack of sustained efficacy, and poor patient convenience as they require parenteral administration. Here, we present designed miniproteins inhibiting IL-23R and IL-17 with antibody-like, low picomolar affinities at a fraction of the molecular size. The minibinders potently block cell signaling in vitro and are extremely stable, enabling oral administration and low-cost manufacturing. The orally administered IL-23R minibinder shows efficacy better than a clinical anti-IL-23 antibody in mouse colitis and has a favorable pharmacokinetics (PK) and biodistribution profile in rats. This work demonstrates that orally administered de novo-designed minibinders can reach a therapeutic target past the gut epithelial barrier. With high potency, gut stability, and straightforward manufacturability, de novo-designed minibinders are a promising modality for oral biologics.

Metabolic coordination between skin epithelium and type 17 immunity sustains chronic skin inflammation.

Inflammatory epithelial diseases are spurred by the concomitant dysregulation of immune and epithelial cells. How these two dysregulated cellular compartments simultaneously sustain their heightened metabolic demands is unclear. Single-cell and spatial transcriptomics (ST), along with immunofluorescence, revealed that hypoxia-inducible factor 1α (HIF1α), downstream of IL-17 signaling, drove psoriatic epithelial remodeling. Blocking HIF1α in human psoriatic lesions ex vivo impaired glycolysis and phenocopied anti-IL-17 therapy. In a murine model of skin inflammation, epidermal-specific loss of HIF1α or its target gene, glucose transporter 1, ameliorated epidermal, immune, vascular, and neuronal pathology. Mechanistically, glycolysis autonomously fueled epithelial pathology and enhanced lactate production, which augmented the γδ T17 cell response. RORγt-driven genetic deletion or pharmacological inhibition of either lactate-producing enzymes or lactate transporters attenuated epithelial pathology and IL-17A expression in vivo. Our findings identify a metabolic hierarchy between epithelial and immune compartments and the consequent coordination of metabolic processes that sustain inflammatory disease.

Access to athletic trainers and sex as modifiers of time to reach clinical milestones after sport-related concussion in collegiate athletes.

OBJECTIVE: Investigate whether an athlete's biological sex and exposure to a dedicated athletic trainer (AT) were related to clinical milestones after a sports-related concussion (SRC). DESIGN: Retrospective chart review. METHODS: Medical charts of collegiate athletes (n = 196 [70.9% female]) diagnosed with SRC were reviewed to extract: biological sex, dedicated AT exposure for their sport (yes/no), and time (days) to reaching clinical milestones (diagnosis, symptom resolution, unrestricted return to sport [RTS]). Mann-Whitney U tests were used to determine whether time to clinical milestones differed by sex, AT exposure, or their interaction. Proportions of same-day diagnoses and times to diagnosis, symptom resolution, and unrestricted RTS were evaluated with chi-squared and spearman's rank correlations, respectively. RESULTS: There were no significant differences in times to reaching any clinical milestone by sex, AT exposure, or their interaction (ps > 0.05). Forty-three percent of participants were diagnosed on the day of their SRC. This did not differ by sex or AT exposure (ps > 0.29). Longer times to SRC diagnosis were associated with more days to symptom resolution (ρ = 0.236, p = 0.001) and unrestricted RTS (ρ = 0.223, p < 0.001). CONCLUSIONS: Athlete sex and AT exposure were not associated with times to reach any clinical milestone; however, delayed diagnosis was associated with longer times to reach clinical recovery.

Sport Type and Risk of Subsequent Injury in Collegiate Athletes Following Concussion: a LIMBIC MATARS Consortium Investigation.

OBJECTIVE: To investigate the association between sport type (collision, contact, non-contact) and subsequent injury risk following concussion in collegiate athletes. MATERIALS AND METHODS: This retrospective chart review of 248 collegiate athletes with diagnosed concussions (age: 20.0 ± 1.4 years; height: 179.6 ± 10.9 cm; mass: 79.0 ± 13.6 kg, 63% male) from NCAA athletic programs (n = 11) occurred between the 2015-2020 athletic seasons. Acute injuries that occurred within six months following concussion were evaluated. Subsequent injuries were grouped by lower extremity, upper extremity, trunk, or concussion. The independent variable was sport type: collision, contact, non-contact. A Cox proportional hazard model was used to assess the risk of subsequent injury between sport types. RESULTS: Approximately 28% (70/248) of athletes sustained a subsequent acute injury within six months post-concussion. Collision sport athletes had a significantly higher risk of sustaining any injury (HR: 0.41, p < 0.001, 95% CI: 0.28, 0.62), lower extremity (HR: 0.55, p = 0.04, 95% CI: 0.32, 0.97), and upper extremity (HR: 0.41, p = 0.01, 95% CI: 0.20, 0.81) injuries following concussion. No differences between sport types were observed for other injuries. CONCLUSION: Collision sport athletes had a higher rate of any subsequent injury, lower, and upper extremity injuries following concussion. Future research should focus on sport-specific secondary injury prevention efforts.

Physical activity and recovery following concussion in collegiate athletes: a LIMBIC MATARS Consortium Investigation.

OBJECTIVE: To investigate whether routine daily activities (RDA), non-prescribed exercise (Non-ERx), or prescribed exercise (ERx) were associated with recovery from sport-related concussion (SRC) in collegiate athletes. MATERIALS AND METHODS: Data for this cross-sectional, retrospective chart review of collegiate athletes diagnosed with SRC (n = 285[39.6% female], age = 19.5 ± 1.4 years) were collected during the 2015-16 to 2019-20 athletic seasons. The independent variable was group (RDA, Non-ERx, ERx). Dependent variables included days from date of diagnosis to symptom resolution (Dx-SR) and SR to return to sport (SR-RTS). RESULTS: Those in the Non-ERx group took nearly 1.3 times longer to achieve SR (IRR = 1.28, 95% CI: 1.11, 1.46) and, 1.8 times longer for RTS (IRR = 1.82, 95% CI: 1.11, 2.71) when compared to those in the RDA group. No other comparisons were significant. CONCLUSION: Collegiate athletes in the Non-ERx group took approximately 1 week longer to achieve SR as compared to the RDA and ERx groups. Our findings suggest that if exercise is recommended following SRC, it must be clearly and specifically prescribed. If exercise parameters cannot be prescribed, or monitored, RDA appear to be similarly beneficial during recovery for collegiate athletes with concussion.

The Influence of Race on Time to Symptom Resolution Following Sport Concussion in Collegiate Athletes.

CONTEXT: Race has been shown to influence computerized neurocognitive test scores, motor function test scores, and reported symptomology following sport-related concussion (SRC). However, the effect race may have on recovery time following SRC remains unknown. The objective of this study was to determine the influence of race on days until symptom free from SRC in NCAA Division 1 collegiate athletes. DESIGN: Prospective cohort study. METHODS: Participants were Black (n = 53 [28% female]) and White (n = 150 [43.3% female]) who were on average 19.0 (1.21) and 20.2 (1.3) years of age, respectively. Data were collected from the 2015-2016 to 2020-2021 collegiate sport seasons. Participants were evaluated before and after an SRC at empirically derived time points. The primary outcome measure was time until symptom free (days). Additional outcomes included baseline and postinjury Immediate Postconcussion Assessment and Cognitive Test and Sensory Organization Test (SOT) scores. A Mann-Whitney U test compared days to symptom free between groups. Immediate Postconcussion Assessment and Cognitive Test and SOT outcome scores were analyzed using a 2 (group) × 2 (time) analysis of variance. RESULTS: White participants had a longer median recovery time (9 d) to symptom free compared with Black participants (6 d [P = .04]). Statistically significant differences were observed between Black 87.3 (9.84) and White 90.4 (8.30) groups for Immediate Postconcussion Assessment and Cognitive Test's verbal memory composite score (P = .03). Postinjury, White participants scored significantly higher 44.5 (5.63) on visual motor speed compared with Black participants (42.4 (5.90) [P = .02]). Within-group SOT differences between baseline and postinjury testing were observed in both groups (all P < .001). CONCLUSIONS: Black collegiate athletes achieved symptom resolution sooner than White athletes. We did not explore underlying sociocultural factors such as socioeconomic status or previous concussion education, which may have influenced our results. Future studies should explore factors that may contextualize these findings.

Roadmap on nanomedicine.

Since the launch of the Alliance for Nanotechnology in Cancer by the National Cancer Institute in late 2004, several similar initiatives have been promoted all over the globe with the intention of advancing the diagnosis, treatment and prevention of cancer in the wake of nanoscience and nanotechnology. All this has encouraged scientists with diverse backgrounds to team up with one another, learn from each other, and generate new knowledge at the interface between engineering, physics, chemistry and biomedical sciences. Importantly, this new knowledge has been wisely channeled towards the development of novel diagnostic, imaging and therapeutic nanosystems, many of which are currently at different stages of clinical development. This roadmap collects eight brief articles elaborating on the interaction of nanomedicines with human biology; the biomedical and clinical applications of nanomedicines; and the importance of patient stratification in the development of future nanomedicines. The first article reports on the role of geometry and mechanical properties in nanomedicine rational design; the second articulates on the interaction of nanomedicines with cells of the immune system; and the third deals with exploiting endogenous molecules, such as albumin, to carry therapeutic agents. The second group of articles highlights the successful application of nanomedicines in the treatment of cancer with the optimal delivery of nucleic acids, diabetes with the sustained and controlled release of insulin, stroke by using thrombolytic particles, and atherosclerosis with the development of targeted nanoparticles. Finally, the last contribution comments on how nanomedicine and theranostics could play a pivotal role in the development of personalized medicines. As this roadmap cannot cover the massive extent of development of nanomedicine over the past 15 years, only a few major achievements are highlighted as the field progressively matures from the initial hype to the consolidation phase.

Harnessing RNAi-based nanomedicines for therapeutic gene silencing in B-cell malignancies.

Despite progress in systemic small interfering RNA (siRNA) delivery to the liver and to solid tumors, systemic siRNA delivery to leukocytes remains challenging. The ability to silence gene expression in leukocytes has great potential for identifying drug targets and for RNAi-based therapy for leukocyte diseases. However, both normal and malignant leukocytes are among the most difficult targets for siRNA delivery as they are resistant to conventional transfection reagents and are dispersed in the body. We used mantle cell lymphoma (MCL) as a prototypic blood cancer for validating a novel siRNA delivery strategy. MCL is an aggressive B-cell lymphoma that overexpresses cyclin D1 with relatively poor prognosis. Down-regulation of cyclin D1 using RNA interference (RNAi) is a potential therapeutic approach to this malignancy. Here, we designed lipid-based nanoparticles (LNPs) coated with anti-CD38 monoclonal antibodies that are specifically taken up by human MCL cells in the bone marrow of xenografted mice. When loaded with siRNAs against cyclin D1, CD38-targeted LNPs induced gene silencing in MCL cells and prolonged survival of tumor-bearing mice with no observed adverse effects. These results highlight the therapeutic potential of cyclin D1 therapy in MCL and present a novel RNAi delivery system that opens new therapeutic opportunities for treating MCL and other B-cell malignancies.

Estimating changes in overdose death rates from increasing methamphetamine supply in Ohio: Evidence from crime lab data.

Background: We investigate the relationship between the supply of methamphetamine and overdose death risk in Ohio. Ohio and the overall US have experienced a marked increase in overdose deaths from methamphetamine combined with fentanyl over the last decade. The increasing use of methamphetamine may be increasing the risk of overdose death. However, if people are using it to substitute away from more dangerous synthetic opioids, it may reduce the overall risk of overdose death. Methods: Ohio's Bureau of Criminal Investigation's crime lab data include a detailed list of the content of drug samples from law enforcement seizures, which are used as a proxy for drug supply. We use linear regressions to estimate the relationship between the proportion of methamphetamine in lab samples and unintentional drug overdose death rates from January 2015 through September 2021. Results: Relatively more methamphetamine in crime lab data in a county-month has either no statistically significant relationship with overdose death rates (in small and medium population counties) or a negative and statistically significant relationship with overdose death rates (in large population counties). Past overdose death rates do not predict future increases in methamphetamine in crime lab data. Conclusions: The results are consistent with a relatively higher supply of methamphetamine reducing the general risk of overdose death, possibly due to substitution away from more dangerous synthetic opioids. However, the supply of methamphetamine appears unrelated to the past illicit drug risk environment. The non-lethal and yet serious health effects of MA use were not explored and, thus, even if the presence of MA reduces the population-level overdose mortality rate, the rise of other adverse health effects may counteract any public health benefits of fewer deaths.

Did the Taliban's opium eradication campaign cause a decline in HIV infections in Russia?

We offer a new hypothesis for why HIV infections fell rapidly after 2001 in Russia: the Taliban's opium eradication campaign in Afghanistan reduced the supply of heroin, causing use to fall and, thus, transmission of HIV to fall. We present evidence of the impact of the eradication campaign on the heroin market and show that the fall in HIV infections happened simultaneously in Russia and surrounding countries soon after the eradication campaign. We also show that the decline in HIV infections only occurred in injecting drug users, while other risk groups were unaffected. Limitations to our analysis are discussed.

False-Positive Rates, Risk Factors, and Interpretations of the Vestibular Ocular Motor Screen in Collegiate Athletes.

CONTEXT: Biological sex and history of motion sickness are known modifiers associated with a false-positive baseline Vestibular Ocular Motor Screen (VOMS). However, other factors may associate with a false-positive VOMS in collegiate athletes. OBJECTIVE: Identify contributing factors to false-positive VOMS assessments using population specific criteria. We also critically appraised previously reported interpretation criterion. DESIGN: Descriptive Laboratory. SETTING: Single site collegiate athletic training clinic. PATIENTS OR OTHER PARTICIPANTS: NCAA Division 1 athletes (n=462[41% female]) who were 18.8±1.4 years old. MAIN OUTCOME MEASURES: Participants completed the Athlete Sleep Behavior Questionnaire (ASBQ), Generalized Anxiety Index (GAD-7), the ImPACT battery, Patient Health Questionnaire (PHQ-9), Revised Head Injury Scale (HIS-r), the Sensory Organization Test (SOT), and the VOMS as part of a multidimensional baseline concussion assessment. Participants were classified into two groups based on whether they had a total symptom score of ≥8 following VOMS administration, excluding the baseline checklist. Chi-squared (χ2) and independent t-tests compared group demographics. A binary logistic regression with adjusted odds ratios (OR) evaluated the influence of sex, corrected vision, ADHD, ImPACT composite scores, concussion history, a history of treatment for headache and/or migraine, GAD-7, PHQ-9, ASBQ, and SOT Equilibrium Score, and Somatosensory, Visual, and Vestibular sensory ratios on false-positive rates. RESULTS: Approximately 9.1% (42/462 [30 females]) met criteria for a false-positive VOMS. A significantly greater proportion of females had false-positives (χ2(1) = 18.37, p < 0.001). Female sex (OR=2.79, 95% CI [1.17-6.65], p =.02) and history of treatment for headache (OR=4.99, 95% CI [1.21-20.59], p=0.026) were the only significant predictors of false-positive VOMS. Depending on cutoff interpretation, false-positive rates using our data ranged from 9.1%-22.5%. CONCLUSIONS: Our results support the most recent interpretation guidelines for the VOMS in collegiate athletes due to a low false-positive rate and ease of interpretation. Biological sex and history of headaches should be considered when administering the VOMS in the absence of a baseline.

Body Mass Index Trends among a Cohort of Subjects Enrolled in Medication-Assisted Treatment Programmes for Opioid Use Disorder: Racial/Ethnic, Gender, and Age Differences.

Introduction: Opioid use disorder (OUD) and obesity are two pressing public health concerns in the United States (US). However, the relationship between these two epidemics has not been well-studied. Our study aims to describe the prevalence rates of obesity in individuals with OUD from a cohort study and compare that to the expected prevalence that would be observed based upon New Jersey state and US population survey data. Additionally, we sought to study whether Body Mass Index (BMI) distribution in this cohort varied by race/ethnicity, gender, and age. Methods: Our subjects (N=151) are part of a drug user cohort study of persons enrolled in medication-assisted treatment (MAT) programmes in New Jersey. Using the New Jersey Behavioral Risk Factor Survey (NJBRFS) and the National Health Interview Survey (NHIS), we generated expected BMI distributions based on race/ethnicity, age, and sex. Expected rates were compared to observed BMI. Standardized prevalence ratios were calculated, and 95% confidence intervals were constructed. Results: Among females, obesity was more prevalent in those with OUD than in the general US population. Among persons ≤50 years old, overweight and obesity were more prevalent in those with OUD than in NJBRFS. Persons who did not inject drugs were more likely to be overweight. The prevalence of underweight was significantly higher among Black non-Hispanic minorities, males, older subjects (aged 66-85), and persons who inject drugs. Conclusion: In our study, the trends in BMI vary based on race/ethnicity, gender and age in these patients with OUD. These varying trends highlight the need for tailored screening and prevention strategies. Primary care providers should be aware that their patients with OUD have multiple health problems that need to be addressed beyond their OUD condition itself. Providers are in a pivotal role to screen and implement interventions to improve their health outcomes.

Epithelial-immune crosstalk in health and disease.

Far from inert structures, our body's epithelial boundaries engage in a dynamic crosstalk with immune cells that is vital for immune surveillance and barrier function. Using the skin and gut epithelium, two structurally distinct but critical environmental interfaces, here we review the context-dependent interactions between myriad immune cells and epithelial subsets. We discuss immune communique reserved for epithelial progenitors and the enduring consequences for tissue fitness. Then, we delve into the cellular and molecular exchanges between differentiated epithelial subsets and adjacent immune cells. Therapeutically targeting stage-specific immune-epithelial interaction could boost regeneration and mitigate inflammatory pathologies.

New dog, old tricks: Developmental programs resurface in inflammation.

Cellular cartography of human tissues has provided unprecedented insight into health and disease. In a recent issue of Science, Reynolds et al. (2021) use single-cell transcriptomics to define cell states and gene programs in human skin and uncover fetal programs in dermatological diseases that may fuel inflammatory pathology.

Therapeutic inhibitory RNA in head and neck cancer via functional targeted lipid nanoparticles.

Currently there are no specific therapies addressing the distinctive biology of human papillomavirus (HPV)-induced cancer approved for clinical use. Short interfering RNA (siRNA) has much potential for therapeutic manipulation of HPV E6/E7 oncoproteins. Lipid-based nanoparticles (LNPs) can be utilized for systemic transportation and delivery of siRNA at target site. We recently developed a recombinant protein linker that enables uniform conjugation of targeting antibodies to the LNPs. Herein, we demonstrate the therapeutic efficacy of anti-E6/E7 siRNA delivered via targeted LNPs (tLNPs) in a xenograft HPV-positive tumor model. We show that anti-epidermal growth factor receptor (EGFR) antibodies, anchored to the LNPs as targeting moieties, facilitate cargo delivery but also mediate anti-tumor activity. Treatment with siE6 via tLNPs resulted in 50% greater reduction of tumor volume compared to treatment with siControl encapsulated in isoLNPs (coated with isotype control antibodies). We demonstrate superior suppression of HPV oncogenes and higher induction of apoptosis by the tLNPs both in vitro and in vivo. Altogether, the coupling of inhibitory siE6 with anti-EGFR antibodies, that further elicited anti-tumor effects, successfully restricted tumor progression. This system that combines potent siRNA and therapeutically functional tLNPs can be modulated against various cancer models.

The Rapidly Changing US Illicit Drug Market and the Potential for an Improved Early Warning System: Evidence from Ohio Drug Crime Labs.

BACKGROUND: The US has seen a rapid increase in synthetic opioid-related overdose deaths. We investigate Ohio, a state with one of the highest overdose death rates in 2017 and substantial numbers of deaths related to fentanyl, carfentanil, and other fentanyl analogs, to provide detailed evidence about the relationship between changes in the illicit drug market and overdose deaths. METHODS: We investigate the illicit drug market using Ohio's Bureau of Criminal Investigation's (BCI) crime lab data from 2009 to 2018 that shows the content of drugs seized by law enforcement. We use Poisson regression analysis to estimate the relationship between monthly crime lab data and monthly unintentional drug overdose death data at the county level. RESULTS: During this time period there has been a rapid change in the composition of drugs analyzed by the BCI labs, with a rapid fall in heroin observations, simultaneous rise in synthetic opioids, and an increase in the number of different fentanyl analogs. We find that the increased presence of fentanyl, carfentanil, and other fentanyl analogs have a strong correlation with an increase in overdose deaths. The types of opioids most associated with deaths varies by the population size of the county. CONCLUSIONS: Crime lab data has the potential to be used as an early warning system to alert persons who inject drugs, harm reduction services, first responders, and law enforcement about changes in the illicit opioid risk environment.

Progress and challenges towards CRISPR/Cas clinical translation.

CRISPR/Cas systems (clustered regularly interspaced short palindromic repeats) have emerged as powerful tools to manipulate the genome for both research and therapeutic purposes. However, the clinical use of this system is hindered by multiple challenges, such as the rate of off-target effects, editing efficiency, the efficacy of HDR, immunogenicity, as well as development of efficient and safe delivery vehicles that can carry these compounds. Tremendous efforts are being conducted to overcome these challenges, including the discovery and engineering of more precise and efficacious Cas nucleases. Moreover, in recent years multiple viral and non-viral delivery approaches have been explored for in vivo delivery of CRISPR components. Here, we summarize the available CRISPR/Cas toolbox for genome editing as well as the recently developed in vivo delivery vehicles for CRISPR/Cas system. Furthermore, we discuss the remaining challenges for successful clinical translation of this system and highlight the current clinical applications.

If Not Now, When? An Absence of Neurocognitive and Postural Stability Deficits in Collegiate Athletes with One or More Concussions.

A history of concussion has been associated with decreased neurocognitive function and postural control. The purpose of our study was to compare neurocognitive function and postural control in collegiate athletes with and without varying histories of concussion. Collegiate athletes were divided into groups based on 0 (n = 129), 1 (n = 91), 2 (n = 52), and 3+ (n = 34) prior concussions. Participants in each group were carefully matched by sport, sex, height, weight, and age. Athletes were administered the Immediate Post-Concussion Assessment and Cognitive Test (ImPACT™) and the Sensory Organization Test (SOT) as part of a standard of care pre-season assessment. Group ImPACT (Verbal and Visual Memory, Visual Motor Speed, and Reaction Time) and SOT (Equilibrium Score and Somatosensory, Visual, and Vestibular sensory ratios) outcome scores were compared using one-way analyses of variance (ANOVAs). Coefficients of variation (CVs) were also calculated for each outcome score and were compared using two-sample tests with 95% confidence intervals (CIs). Participants with and without a history of concussion were not significantly different for any ImPACT or SOT outcome score (p's > 0.10). Groups (0, 1, 2, and 3+ previous concussions) were not different from each other for any ImPACT or SOT outcome score (p's ≥ 0.11). Likewise, the CVs associated with each ImPACT and SOT outcome score did not vary significantly between outcome scores for any group comparison (p ≥ 0.09). Our findings suggest that a history of one or more concussions does not influence neurocognitive performance or postural stability in collegiate athletes at their pre-season baseline assessment.

CRISPR-Cas9 genome editing using targeted lipid nanoparticles for cancer therapy.

Harnessing CRISPR-Cas9 technology for cancer therapeutics has been hampered by low editing efficiency in tumors and potential toxicity of existing delivery systems. Here, we describe a safe and efficient lipid nanoparticle (LNP) for the delivery of Cas9 mRNA and sgRNAs that use a novel amino-ionizable lipid. A single intracerebral injection of CRISPR-LNPs against PLK1 (sgPLK1-cLNPs) into aggressive orthotopic glioblastoma enabled up to ~70% gene editing in vivo, which caused tumor cell apoptosis, inhibited tumor growth by 50%, and improved survival by 30%. To reach disseminated tumors, cLNPs were also engineered for antibody-targeted delivery. Intraperitoneal injections of EGFR-targeted sgPLK1-cLNPs caused their selective uptake into disseminated ovarian tumors, enabled up to ~80% gene editing in vivo, inhibited tumor growth, and increased survival by 80%. The ability to disrupt gene expression in vivo in tumors opens new avenues for cancer treatment and research and potential applications for targeted gene editing of noncancerous tissues.

Resveratrol Enhances mRNA and siRNA Lipid Nanoparticles Primary CLL Cell Transfection.

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western populations. Therapies such as mRNA and siRNA encapsulated in lipid nanoparticles (LNPs) represent a clinically advanced platform and are utilized for a wide variety of applications. Unfortunately, transfection of RNA into CLL cells remains a formidable challenge and a bottleneck for developing targeted therapies for this disease. Therefore, we aimed to elucidate the barriers to efficient transfection of RNA-encapsulated LNPs into primary CLL cells to advance therapies in the future. To this end, we transfected primary CLL patient samples with mRNA and siRNA payloads encapsulated in an FDA-approved LNP formulation and characterized the transfection. Additionally, we tested the potential of repurposing caffeic acid, curcumin and resveratrol to enhance the transfection of nucleic acids into CLL cells. The results demonstrate that the rapid uptake of LNPs is required for successful transfection. Furthermore, we demonstrate that resveratrol enhances the delivery of both mRNA and siRNA encapsulated in LNPs into primary CLL patient samples, overcoming inter-patient heterogeneity. This study points out the important challenges to consider for efficient RNA therapeutics for CLL patients and advocates the use of resveratrol in combination with RNA lipid nanoparticles to enhance delivery into CLL cells.