In vivo perturb-seq of cancer and microenvironment cells dissects oncologic drivers and radiotherapy responses in glioblastoma.

BACKGROUND: Genetic perturbation screens with single-cell readouts have enabled rich phenotyping of gene function and regulatory networks. These approaches have been challenging in vivo, especially in adult disease models such as cancer, which include mixtures of malignant and microenvironment cells. Glioblastoma (GBM) is a fatal cancer, and methods of systematically interrogating gene function and therapeutic targets in vivo, especially in combination with standard of care treatment such as radiotherapy, are lacking. RESULTS: Here, we iteratively develop a multiplex in vivo perturb-seq CRISPRi platform for single-cell genetic screens in cancer and tumor microenvironment cells that leverages intracranial convection enhanced delivery of sgRNA libraries into mouse models of GBM. Our platform enables potent silencing of drivers of in vivo growth and tumor maintenance as well as genes that sensitize GBM to radiotherapy. We find radiotherapy rewires transcriptional responses to genetic perturbations in an in vivo-dependent manner, revealing heterogenous patterns of treatment sensitization or resistance in GBM. Furthermore, we demonstrate targeting of genes that function in the tumor microenvironment, enabling alterations of ligand-receptor interactions between immune and stromal cells following in vivo CRISPRi perturbations that can affect tumor cell phagocytosis. CONCLUSION: In sum, we demonstrate the utility of multiplexed perturb-seq for in vivo single-cell dissection of adult cancer and normal tissue biology across multiple cell types in the context of therapeutic intervention, a platform with potential for broad application.

Return to play and performance after patellar fracture in American professional sports: a case-control cohort analysis.

OBJECTIVES: This study describes the effects of patellar fracture on return to play (RTP) and functional outcomes among athletes in American professional sports. METHODS: Professional athletes from the National Football League (NFL), National Basketball Association (NBA), Major League Baseball (MLB), and National Hockey League (NHL) who suffered a patellar fracture between January 1965 and December 2021 were identified through injury reports and public archives. Performance scores, play time, and games played were collected for the season preceding patellar fracture and 2 seasons after RTP, and differences in recorded metrics compared to pre-injury levels and matched controls were analyzed. RESULTS: Twenty-nine of 41 (71%) injured athletes returned to play at an average of 217 days. Among all players, play volume decreased in year 1 compared to baseline but recovered to pre-injury levels in year 2. Athletes treated operatively experienced an initial decline in performance (p < 0.01) but recovered to pre-injury performance level in year 2. Nonoperative management resulted in a decline in performance in year 2 of RTP (p = 0.02). Athletes treated operatively performed significantly worse than matched controls in year 1 of RTP (64% vs. 99%; p = 0.04) but recovered to a similar level of performance as controls in year 2 (87% vs. 91%; p = 0.90). CONCLUSION: A 71% rate of RTP was demonstrated among this limited cohort of 29 athletes in American professional sports after isolated patellar fracture. Although details regarding fracture characteristics and operative reports were not available for analysis, operative management was not associated with longer absence from play compared to nonoperative treatment. Despite the limitations of this study, the findings suggesting operative management may improve prospects of maintaining elite performance following RTP warrant further investigation. LEVEL OF EVIDENCE: Case-control cohort analysis; Level of evidence, 3.

EGFR and EGFRvIII coopt host defense pathways, promoting progression in glioblastoma.

BACKGROUND: Co-amplification of EGFR and EGFRvIII, a tumor-specific truncation mutant of EGFR, represent hallmark genetic lesions in glioblastoma. METHODS: We used phospho-proteomics, RNA-sequencing, TCGA data and glioblastoma cell culture and mouse models to study the signal transduction mediated by EGFR and EGFRvIII. RESULTS: We report that EGFR and EGFRvIII stimulate the innate immune defense receptor Toll-like Receptor 2 (TLR2); and that knockout of TLR2 dramatically improved survival in orthotopic glioblastoma xenografts. EGFR and EGFRvIII activated TLR2 in a ligand-independent manner, promoting tumor growth and immune evasion. We show that EGFR and EGFRvIII cooperate to activate the Rho-associated protein kinase ROCK2, which modulated malignant progression both by activating TLR2 and WNT signaling, and through remodeling the tumor microenvironment. CONCLUSION: Together, our findings show that EGFR and EGFRvIII cooperate to drive tumor progression through ROCK2 and downstream WNT-ß-catenin/TLR2 signaling pathways.

Preventing Iatrogenic Fibula Fractures Using the Push-Pull Technique: A Biomechanical Comparison of Unicortical Versus Bicortical Post Screws.

BACKGROUND: Displaced diaphyseal fractures can be reduced using the push-pull technique, wherein a plate is affixed to the distal fragment of the fracture, a post screw is placed proximal to the plate, and a lamina spreader creates distraction. This study evaluated the load to failure and mechanism of failure of bicortical and unicortical post screws during reduction. MATERIALS AND METHODS: Four matched pairs of cadaver legs were subjected to a 2-cm oblique osteotomy simulating a displaced, oblique diaphyseal fracture. A 6-hole compression plate was affixed to the distal fragment with 2 unicortical locking screws, and a 12-mm unicortical or 20-mm bicortical screw was inserted as a post screw proximal to the plate. A lamina bone spreader was used to exert a distraction force between the plate and the post screw. A mechanical actuator simulated the distraction procedure until failure. Maximum applied load, displacement, and absorbed energy were recorded and compared across unicortical and bicortical groups by paired t tests. RESULTS: At maximum load, we found statistically significant differences in displacement (P=.003) and energy absorbed (P=.022) between the two groups. All unicortical screws failed through screw toggle and bone cut-out. Bicortical screws failed through bending, with no visible damage to the bone at the screw site. CONCLUSION: When diaphyseal fractures are significantly shortened and require a greater distraction force to achieve reduction, bicortical screws demonstrate a higher mechanical load to failure and increased bone loss from the screw-removal site. A unicortical post screw may be used if minimal distraction is needed. [Orthopedics. 2024;47(5):308-312.].

PRDM6 promotes medulloblastoma by repressing chromatin accessibility and altering gene expression.

SNCAIP duplication may promote Group 4 medulloblastoma via induction of PRDM6, a poorly characterized member of the PRDF1 and RIZ1 homology domain-containing (PRDM) family of transcription factors. Here, we investigated the function of PRDM6 in human hindbrain neuroepithelial stem cells and tested PRDM6 as a driver of Group 4 medulloblastoma. We report that human PRDM6 localizes predominantly to the nucleus, where it causes widespread repression of chromatin accessibility and complex alterations of gene expression patterns. Genome-wide mapping of PRDM6 binding reveals that PRDM6 binds to chromatin regions marked by histone H3 lysine 27 trimethylation that are located within, or proximal to, genes. Moreover, we show that PRDM6 expression in neuroepithelial stem cells promotes medulloblastoma. Surprisingly, medulloblastomas derived from PRDM6-expressing neuroepithelial stem cells match human Group 3, but not Group 4, medulloblastoma. We conclude that PRDM6 expression has oncogenic potential but is insufficient to drive Group 4 medulloblastoma from neuroepithelial stem cells. We propose that both PRDM6 and additional factors, such as specific cell-of-origin features, are required for Group 4 medulloblastoma. Given the lack of PRDM6 expression in normal tissues and its oncogenic potential shown here, we suggest that PRDM6 inhibition may have therapeutic value in PRDM6-expressing medulloblastomas.

Aurora Kinase A inhibition enhances DNA damage and tumor cell death with 131I-MIBG therapy in high-risk neuroblastoma.

BACKGROUND: Neuroblastoma is the most common extra-cranial pediatric solid tumor. 131I-metaiodobenzylguanidine (MIBG) is a targeted radiopharmaceutical highly specific for neuroblastoma tumors, providing potent radiotherapy to widely metastatic disease. Aurora kinase A (AURKA) plays a role in mitosis and stabilization of the MYCN protein in neuroblastoma. We aimed to study the impact of AURKA inhibitors on DNA damage and tumor cell death in combination with 131I-MIBG therapy in a pre-clinical model of high-risk neuroblastoma. RESULTS: Using an in vivo model of high-risk neuroblastoma, we demonstrated a marked combinatorial effect of 131I-MIBG and alisertib on tumor growth. In MYCN amplified cell lines, the combination of radiation and an AURKA A inhibitor increased DNA damage and apoptosis and decreased MYCN protein levels. CONCLUSION: The combination of AURKA inhibition with 131I-MIBG treatment is active in resistant neuroblastoma models.

MYC phase separation selectively modulates the transcriptome.

Dysregulation and enhanced expression of MYC transcription factors (TFs) including MYC and MYCN contribute to the majority of human cancers. For example, MYCN is amplified up to several hundredfold in high-risk neuroblastoma. The resulting overexpression of N-myc aberrantly activates genes that are not activated at low N-myc levels and drives cell proliferation. Whether increasing N-myc levels simply mediates binding to lower-affinity binding sites in the genome or fundamentally changes the activation process remains unclear. One such activation mechanism that could become important above threshold levels of N-myc is the formation of aberrant transcriptional condensates through phase separation. Phase separation has recently been linked to transcriptional regulation, but the extent to which it contributes to gene activation remains an open question. Here we characterized the phase behavior of N-myc and showed that it can form dynamic condensates that have transcriptional hallmarks. We tested the role of phase separation in N-myc-regulated transcription by using a chemogenetic tool that allowed us to compare non-phase-separated and phase-separated conditions at equivalent N-myc levels, both of which showed a strong impact on gene expression compared to no N-myc expression. Interestingly, we discovered that only a small percentage (<3%) of N-myc-regulated genes is further modulated by phase separation but that these events include the activation of key oncogenes and the repression of tumor suppressors. Indeed, phase separation increases cell proliferation, corroborating the biological effects of the transcriptional changes. However, our results also show that >97% of N-myc-regulated genes are not affected by N-myc phase separation, demonstrating that soluble complexes of TFs with the transcriptional machinery are sufficient to activate transcription.

Fluid Dynamic Study of the Penn State Pediatric Total Artificial Heart.

Penn State University is developing a pediatric total artificial heart (TAH) as a bridge-to-transplant device that supports infants and small children with single ventricle anomalies or biventricular heart failure to address high waitlist mortality rates for pediatric patients with severe congenital heart disease (CHD). Two issues with mechanical circulatory support devices are thrombus formation and thromboembolic events. This in vitro study characterizes flow within Penn State's pediatric total artificial heart under physiological operating conditions. Particle image velocimetry (PIV) is used to quantify flow within the pump and to calculate wall shear rates (WSRs) along the internal pump surface to identify potential thrombogenic regions. Results show that the diastolic inflow jets produce sufficient wall shear rates to reduce thrombus deposition potential along the inlet side of the left and right pumps. The inlet jet transitions to rotational flow, which promotes wall washing along the apex of the pumps, prevents flow stasis, and aligns flow with the outlet valve prior to systolic ejection. However, inconsistent high wall shear rates near the pump apex cause increased thrombogenic potential. Strong systolic outflow jets produce high wall shear rates near the outlet valve to reduce thrombus deposition risk. The right pump, which has a modified outlet port angle to improve anatomical fit, produces lower wall shear rates and higher thrombus susceptibility potential (TSP) compared to the left pump. In summary, this study provides a fluid dynamic understanding of a new pediatric total artificial heart and indicates thrombus susceptibility is primarily confined to the apex, consistent with similar pulsatile heart pumps.

Development of the PSU Child Pump.

The Pennsylvania State University (PSU) Child Pump, a centrifugal continuous-flow ventricular assist device (cf-VAD), is being developed as a suitable long-term implantable device for pediatric heart failure patients between 10 and 35 kg, body surface area (BSA) of 0.5-1.2 m 2 , 1-11 years of age, and requiring a mean cardiac output of 1.0-3.5 L/min. In-vitro hydraulic and hemodynamic performances were evaluated on a custom mock circulatory loop with ovine blood. Normalized index of hemolysis (NIH) was evaluated under four conditions: 1) 8,300 rpm, 3.5 L/min, Δ P = 60 mm Hg, 2) 8,150 rpm, 5.1 L/min, Δ P = 20 mm Hg, 3) 8,400 rpm, 3.2 L/min, Δ P = 70 mm Hg, and 4) 9,850 rpm, 5.0 L/min, Δ P = 80 mm Hg, resulting in normalized index of hemolysis = 0.027 ± 0.013, 0.015 ± 0.006, 0.016 ± 0.008, and 0.026 ± 0.011 mg/dl, respectively. A mock fit study was conducted using a three-dimensional printed model of a 19 kg patient's thoracic cavity to compare the size of the PSU Child Pump to the HeartMate3 and the HVAD. Results indicate the PSU Child Pump will be a safer, appropriately sized device capable of providing the given patient cohort proper support while minimizing the risks of blood trauma as they wait for a transplant.

ALK upregulates POSTN and WNT signaling to drive neuroblastoma.

Neuroblastoma is the most common extracranial solid tumor of childhood. While MYCN and mutant anaplastic lymphoma kinase (ALKF1174L) cooperate in tumorigenesis, how ALK contributes to tumor formation remains unclear. Here, we used a human stem cell-based model of neuroblastoma. Mis-expression of ALKF1174L and MYCN resulted in shorter latency compared to MYCN alone. MYCN tumors resembled adrenergic, while ALK/MYCN tumors resembled mesenchymal, neuroblastoma. Transcriptomic analysis revealed enrichment in focal adhesion signaling, particularly the extracellular matrix genes POSTN and FN1 in ALK/MYCN tumors. Patients with ALK-mutant tumors similarly demonstrated elevated levels of POSTN and FN1. Knockdown of POSTN, but not FN1, delayed adhesion and suppressed proliferation of ALK/MYCN tumors. Furthermore, loss of POSTN reduced ALK-dependent activation of WNT signaling. Reciprocally, inhibition of the WNT pathway reduced expression of POSTN and growth of ALK/MYCN tumor cells. Thus, ALK drives neuroblastoma in part through a feedforward loop between POSTN and WNT signaling.

Aurora Kinase A inhibition enhances DNA damage and tumor cell death with 131I-MIBG therapy in high-risk neuroblastoma.

Background: Neuroblastoma is the most common extra-cranial pediatric solid tumor. 131I-metaiodobenzylguanidine (MIBG) is a targeted radiopharmaceutical highly specific for neuroblastoma tumors, providing potent radiotherapy to widely metastatic disease. Aurora kinase A (AURKA) plays a role in mitosis and stabilization of the MYCN protein in neuroblastoma. Here we explore whether AURKA inhibition potentiates a response to MIBG therapy. Results: Using an in vivo model of high-risk neuroblastoma, we demonstrated a marked combinatorial effect of 131I-MIBG and alisertib on tumor growth. In MYCN amplified cell lines, the combination of radiation and an AURKA A inhibitor increased DNA damage and apoptosis and decreased MYCN protein levels. Conclusion: The combination of AURKA inhibition with 131I-MIBG treatment is active in resistant neuroblastoma models and is a promising clinical approach in high-risk neuroblastoma.

Phenytoin is associated with increased risk of osteoporosis and fragility fractures in adult epileptic patients.

INTRODUCTION: Osteoporotic fractures lead to significant decreases in the quality of life with increases in morbidity, mortality, and disability. Treatment with a variety of anti-epileptic drugs, such as phenytoin, has been understood to cause a decrease in bone mineral density. MATERIALS AND METHODS: Cohort A was identified as patients that were 18-55 years old that had epilepsy and recurrent seizures that were also prescribed phenytoin. Cohort B was identified as patients that were 18-55 years old that had epilepsy and recurrent seizures but were not prescribed phenytoin or other anti-epileptic medications. Cohorts were matched for relevant confounding pathologies and demographic factors. Outcomes were evaluated from 1 day to 5 years after the indexed event. RESULTS: A total of 35,936 patients with epilepsy that were prescribed phenytoin were matched with 109,335 patients with epilepsy that were not prescribed phenytoin. Patients on phenytoin therapy were at significantly higher risk for osteoporosis without pathological fracture, fracture of metatarsal bone, fracture of shoulder and upper arm, fracture of distal radius, fracture of thoracic vertebra, fracture of cervical vertebra, fracture of lumbar vertebra, fracture of femoral head or neck, pertrochanteric fracture, femoral shaft fracture, and distal tibia fracture (all outcomes p < 0.001). CONCLUSION: Epileptic patients on phenytoin therapy that were 18-55 years old exhibited higher associated risk of osteoporosis and osteoporotic-fragility fractures of various regions. Patients that undergo phenytoin therapy for epilepsy treatment should be educated on the increased risk of bone fractures and have appropriate lifestyle and diet modifications.

Risk Factors Associated With Postoperative Cardiac Events Following Total Hip and Knee Arthroplasty.

BACKGROUND: This study investigated the prevalence of adverse cardiac events following a total joint arthroplasty and subsequently analyzed risk factors that may increase the likelihood of these events. METHODS: Data for this study were extracted from a large national database. Chi-squared analyses and multivariate modelings were performed to determine the risk factors associated with 30-day perioperative troponin elevation, myocardial infarction (MI), and heart failure. We identified 80,544 total hip arthroplasty (THA) patients and 112,531 total knee arthroplasty (TKA) patients and analyzed the following cardiac risk factors: diabetes, renal insufficiency, prior MI, hypertension, and cerebrovascular disease. RESULTS: There were 34% of THA patients and 52% of TKA patients who had at least one of the studied risk factors. At-risk THA patients had 2.2, 5.9, and 5.3 times the odds of troponin elevation, MI, and postoperative heart failure, respectively, within 1 month compared to the control group (P < .0001). The TKA group had 2.9, 5.3, and 5.9 times the odds of troponin elevation, MI, and postoperative heart failure within 1 month compared to the control group (P < .0001). For both procedures, prior MI had the highest odds of resulting in perioperative troponin elevation and MI. Renal insufficiency had the highest odds of resulting in perioperative heart failure. CONCLUSIONS: Risk stratification for postoperative complications in orthopedic surgery is important to minimize adverse outcomes. This study highlights the need for consideration of risk factors prior to joint arthroplasty surgery. LEVEL OF EVIDENCE: Level III, Prognostic.

Spinal Muscular Atrophy Type 1 Survival Without New Pharmacotherapies: Two Treatment Paradigms.

OBJECTIVES: The aims of the study are to present noninvasive respiratory management outcomes using continuous noninvasive ventilatory support and mechanical in-exsufflation from infancy for spinal muscular atrophy type 1 and to consider bearing on new medical therapies. DESIGN: Noninvasive ventilatory support was begun for consecutively referred symptomatic infants with spinal muscular atrophy type 1 from 1 to 10 mos of age. Intercurrent episodes of respiratory failure were managed by intubation then extubation to continuous noninvasive ventilatory support and mechanical in-exsufflation despite failing ventilator weaning and extubation attempts. Intubations, tracheotomies, and survival were monitored. RESULTS: Of 153 patients with spinal muscular atrophy 1 consecutively referred since 1995, 37 became continuous noninvasive ventilatory support dependent, almost half before 10 yrs of age. Of the 37, 18 required continuous noninvasive ventilatory support for a mean 18.6 ± 3.3 yrs to a mean 25.3 (range, 18-30) yrs of age, dependent from as young as 4 mos of age with 0 to 40 ml of vital capacity. One of the 18 died from COVID-19 acute respiratory distress syndrome at age 24 after 23 yrs of continuous noninvasive ventilatory support. Extubation success rate of 85% per attempt (150/176) resulted in only one undergoing tracheotomy. CONCLUSIONS: Medical treatments begun during the first 6 wks of age convert spinal muscular atrophy 1 into spinal muscular atrophy 2 or 3 but cough flows remain inadequate to avoid many pneumonias that, once resolved by a treatment paradigm of extubation to continuous noninvasive ventilatory support and mechanical in-exsufflation, eliminates need to resort to tracheotomies.

Return to Play Rates Following Operative Ankle Fractures Differ Between High- and Low-Performing National Football League Athletes.

This study investigated predictive factors for return to play among National Football League athletes after operative treatment of ankle fractures and the impacts of these injuries on career longevity and player performance. Athletes who underwent surgery to repair ankle fractures from the 2013 to 2017 seasons were identified from injury reserve lists and press releases. Demographics and season metrics were collected before and after the injury. Statistical analysis assessed for differences in recorded variables between injured and uninjured players. Thirty-one players met study inclusion criteria. Twenty-two (71%) athletes successfully returned to play. Players who did not return showed no significant differences (P>.05) in position, age, body mass index, number of games or seasons played preinjury, or snaps per game the season prior to injury and had a significantly lower (42.6%, P=.013) preinjury season approximate value (SAV) compared with returning players. Returning athletes showed no significant differences (P>.05) in SAV or snaps per game compared with their preinjury season or with uninjured controls. A high preinjury SAV is associated with successful return to play. No difference in game time or performance metrics was detectable between returning players and uninjured controls, or between preinjury and postinjury seasons. [Orthopedics. 2024;47(1):22-27.].

Development and validation of a rabbit model of Pseudomonas aeruginosa non-ventilated pneumonia for preclinical drug development.

Background: New drugs targeting antimicrobial resistant pathogens, including Pseudomonas aeruginosa, have been challenging to evaluate in clinical trials, particularly for the non-ventilated hospital-acquired pneumonia and ventilator-associated pneumonia indications. Development of new antibacterial drugs is facilitated by preclinical animal models that could predict clinical efficacy in patients with these infections. Methods: We report here an FDA-funded study to develop a rabbit model of non-ventilated pneumonia with Pseudomonas aeruginosa by determining the extent to which the natural history of animal disease reproduced human pathophysiology and conducting validation studies to evaluate whether humanized dosing regimens of two antibiotics, meropenem and tobramycin, can halt or reverse disease progression. Results: In a rabbit model of non-ventilated pneumonia, endobronchial challenge with live P. aeruginosa strain 6206, but not with UV-killed Pa6206, caused acute respiratory distress syndrome, as evidenced by acute lung inflammation, pulmonary edema, hemorrhage, severe hypoxemia, hyperlactatemia, neutropenia, thrombocytopenia, and hypoglycemia, which preceded respiratory failure and death. Pa6206 increased >100-fold in the lungs and then disseminated from there to infect distal organs, including spleen and kidneys. At 5 h post-infection, 67% of Pa6206-challenged rabbits had PaO2 <60 mmHg, corresponding to a clinical cut-off when oxygen therapy would be required. When administered at 5 h post-infection, humanized dosing regimens of tobramycin and meropenem reduced mortality to 17-33%, compared to 100% for saline-treated rabbits (P<0.001 by log-rank tests). For meropenem which exhibits time-dependent bactericidal activity, rabbits treated with a humanized meropenem dosing regimen of 80 mg/kg q2h for 24 h achieved 100% T>MIC, resulting in 75% microbiological clearance rate of Pa6206 from the lungs. For tobramycin which exhibits concentration-dependent killing, rabbits treated with a humanized tobramycin dosing regimen of 8 mg/kg q8h for 24 h achieved Cmax/MIC of 9.8 ± 1.4 at 60 min post-dose, resulting in 50% lung microbiological clearance rate. In contrast, rabbits treated with a single tobramycin dose of 2.5 mg/kg had Cmax/MIC of 7.8 ± 0.8 and 8% (1/12) microbiological clearance rate, indicating that this rabbit model can detect dose-response effects. Conclusion: The rabbit model may be used to help predict clinical efficacy of new antibacterial drugs for the treatment of non-ventilated P. aeruginosa pneumonia.

HeartWare Left Ventricular Assist Device Exercise Hemodynamics With Speed Adjustment Based on Left Ventricular Filling Pressures.

Functional capacity remains limited in heart failure patients with left ventricular assist devices (LVADs) due to fixed pump speed and inability to offload the left ventricle adequately. We hypothesized that manually adjusting LVAD speed during exercise based on pulmonary capillary wedge pressures would increase total cardiac output and maximal oxygen consumption. Two participants with a HeartWare LVAD underwent an invasive ramp study at rest followed by an invasive cardiopulmonary stress test exercising in two randomized phases: fixed speed and adjusted speed. In the latter phase, speed was adjusted every 1 minute during exercise at ±20 rpm/1 mm Hg change from baseline pulmonary capillary wedge pressure. There was no difference in maximal oxygen consumption between the two phases, with a modest increase in total cardiac output during speed adjustment. Filling pressures were initially controlled during speed adjustment until speed was capped at 4,000 rpm, at which point filling pressures increased. Blood pressure was variable. The pressure across the head of the pump (ΔP) was higher with speed adjustment. Contrary to our hypothesis, LVAD speed adjustment during exercise did not improve total cardiac output and functional capacity. This variable response may be attributed to the native cardiac reserve and baroreceptor response; however, additional studies are needed.

An mRNA-based platform for the delivery of pathogen-specific IgA into mucosal secretions.

Colonization of the gut and airways by pathogenic bacteria can lead to local tissue destruction and life-threatening systemic infections, especially in immunologically compromised individuals. Here, we describe an mRNA-based platform enabling delivery of pathogen-specific immunoglobulin A (IgA) monoclonal antibodies into mucosal secretions. The platform consists of synthetic mRNA encoding IgA heavy, light, and joining (J) chains, packaged in lipid nanoparticles (LNPs) that express glycosylated, dimeric IgA with functional activity in vitro and in vivo. Importantly, mRNA-derived IgA had a significantly greater serum half-life and a more native glycosylation profile in mice than did a recombinantly produced IgA. Expression of an mRNA encoded Salmonella-specific IgA in mice resulted in intestinal localization and limited Peyer's patch invasion. The same mRNA-LNP technology was used to express a Pseudomonas-specific IgA that protected from a lung challenge. Leveraging the mRNA antibody technology as a means to intercept bacterial pathogens at mucosal surfaces opens up avenues for prophylactic and therapeutic interventions.