An expanded chronic care management approach to multiple chronic conditions in Hispanics using community health workers as community extenders in the Rio Grande Valley of Texas.

INTRODUCTION: The synergistic negative effects of type 2 diabetes (T2DM) and hypertension increases all-cause mortality and the medical complexity of management, which disproportionately impact Hispanics who face barriers to healthcare access. The Salud y Vida intervention was delivered to Hispanic adults living along the Texas-Mexico Border with comorbid poorly controlled T2DM and hypertension. The Salud y Vida multicomponent intervention incorporated community health workers (CHWs) into an expanded chronic care management model to deliver home-based follow-up visits and provided community-based diabetes self-management education. METHODS: We conducted multivariable longitudinal analysis to examine the longitudinal intervention effect on reducing systolic and diastolic blood pressure among 3806 participants enrolled between 2013 and 2019. Participants were compared according to their program participation as either higher (≥ 10 combined educational classes and CHW visits) or lower engagement (<10 encounters). Data was collected between 2013 and 2020. RESULTS: Baseline mean systolic and diastolic blood pressure were 138 and 81 mmHg respectively. There were overall improvements in systolic (-6.49; 95% CI = [-7.13, -5.85]; p < 0.001) and diastolic blood pressure (-3.97; 95% CI = [-4.37, -3.56]; p < 0.001). The higher engagement group had greater systolic blood pressure reduction at 3 months (adjusted mean difference = -1.8 mmHg; 95% CI = [-3.2, -0.3]; p = 0.016) and at 15 month follow-up (adjusted mean difference = -2.3 mmHg; 95% CI = [-4.2, -0.39]; p = 0.0225) compared to the lower engagement group. CONCLUSION: This intervention, tested and delivered in a real-world setting, provides an example of how CHW integration into an expanded chronic care model can improve blood pressure outcomes for individuals with co-morbidities.

Efficient Gene Editing for Heart Disease via ELIP-Based CRISPR Delivery System.

Liposomes as carriers for CRISPR/Cas9 complexes represent an attractive approach for cardiovascular gene therapy. A critical barrier to this approach remains the efficient delivery of CRISPR-based genetic materials into cardiomyocytes. Echogenic liposomes (ELIP) containing a fluorescein isothiocyanate-labeled decoy oligodeoxynucleotide against nuclear factor kappa B (ELIP-NF-κB-FITC) were used both in vitro on mouse neonatal ventricular myocytes and in vivo on rat hearts to assess gene delivery efficacy with or without ultrasound. In vitro analysis was then repeated with ELIP containing Cas9-sg-IL1RL1 (interleukin 1 receptor-like 1) RNA to determine the efficiency of gene knockdown. ELIP-NF-κB-FITC without ultrasound showed limited gene delivery in vitro and in vivo, but ultrasound combined with ELIP notably improved penetration into heart cells and tissues. When ELIP was used to deliver Cas9-sg-IL1RL1 RNA, gene editing was successful and enhanced by ultrasound. This innovative approach shows promise for heart disease gene therapy using CRISPR technology.

Simultaneous submission of seven CTSA proposals: UM1, K12, R25, T32-predoctoral, T32-postdoctoral, and RC2: strategies, evaluation, and lessons learned.

Translation is the process of turning observations in the research laboratory, clinic, and community into interventions that improve people's health. The Clinical and Translational Science Awards (CTSA) program is a National Center for Advancing Translational Sciences (NCATS) initiative to advance translational science and research. Currently, 64 "CTSA hubs" exist across the nation. Since 2006, the Houston-based Center for Clinical Translational Sciences (CCTS) has assembled a well-integrated, high-impact hub in Texas that includes six partner institutions within the state, encompassing ∼23,000 sq. miles and over 16 million residents. To achieve the NCATS goal of "more treatments for all people more quickly," the CCTS promotes diversity and inclusion by integrating underrepresented populations into clinical studies, workforce training, and career development. In May 2023, we submitted the UM1 application and six "companion" proposals: K12, R25, T32-Predoctoral, T32-Postdoctoral, and RC2 (two applications). In October 2023, we received priority scores for the UM1 (22), K12 (25), T32-Predoctoral (20), and T32-Postdoctoral (23), which historically fall within the NCATS funding range. This report describes the grant preparation and submission approach, coupled with data from an internal survey designed to assimilate feedback from principal investigators, writers, reviewers, and administrative specialists. Herein, we share the challenges faced, the approaches developed, and the lessons learned.

Biomechanical Evaluation of Aortic Valve Stenosis by Means of a Virtual Stress Test: A Fluid-Structure Interaction Study.

The impact of aortic valve stenosis (AS) extends beyond the vicinity of the narrowed leaflets into the left ventricle (LV) and into the systemic vasculature because of highly unpredictable valve behavior and complex blood flow in the ascending aorta that can be attributed to the strong interaction between the narrowed cusps and the ejected blood. These effects can become exacerbated during exercise and may have implications for disease progression, accurate diagnosis, and timing of intervention. In this 3-D patient-specific study, we employ strongly coupled fluid-structure interaction (FSI) modeling to perform a comprehensive biomechanical evaluation of systolic ejection dynamics in a stenosed aortic valve (AV) during increasing LV contraction. Our model predictions reveal that the heterogeneous ∆P vs. Q relationship that was observed in our previous clinical study can be attributed to a non-linear increase (by ~ 1.5-fold) in aortic valve area as LV heart rate increases from 70 to 115 bpm. Furthermore, our results show that even for a moderately stenotic valve, increased LV contraction during exercise can lead to high-velocity flow turbulence (Re = 11,700) in the aorta similar to that encountered with a severely stenotic valve (Re ~ 10,000), with concomitant greater viscous loss (~3-fold increase) and elevated wall stress in the ascending aorta. Our FSI predictions also reveal that individual valve cusps undergo distinct and highly non-linear increases (>100%) in stress during exercise, potentially contributing to progressive calcification. Such quantitative biomechanical evaluations from realistic FSI workflows provide insights into disease progression and can be integrated with current stress testing for AS patients to comprehensively predict hemodynamics and valve function under both baseline and exercise conditions.

Coronary flow capacity and survival prediction after revascularization: physiological basis and clinical implications.

BACKGROUND AND AIMS: Coronary flow capacity (CFC) is associated with an observed 10-year survival probability for individual patients before and after actual revascularization for comparison to virtual hypothetical ideal complete revascularization. METHODS: Stress myocardial perfusion (mL/min/g) and coronary flow reserve (CFR) per pixel were quantified in 6979 coronary artery disease (CAD) subjects using Rb-82 positron emission tomography (PET) for CFC maps of artery-specific size-severity abnormalities expressed as percent left ventricle with prospective follow-up to define survival probability per-decade as fraction of 1.0. RESULTS: Severely reduced CFC in 6979 subjects predicted low survival probability that improved by 42% after revascularization compared with no revascularization for comparable severity (P = .0015). For 283 pre-and-post-procedure PET pairs, severely reduced regional CFC-associated survival probability improved heterogeneously after revascularization (P < .001), more so after bypass surgery than percutaneous coronary interventions (P < .001) but normalized in only 5.7%; non-severe baseline CFC or survival probability did not improve compared with severe CFC (P = .00001). Observed CFC-associated survival probability after actual revascularization was lower than virtual ideal hypothetical complete post-revascularization survival probability due to residual CAD or failed revascularization (P < .001) unrelated to gender or microvascular dysfunction. Severely reduced CFC in 2552 post-revascularization subjects associated with low survival probability also improved after repeat revascularization compared with no repeat procedures (P = .025). CONCLUSIONS: Severely reduced CFC and associated observed survival probability improved after first and repeat revascularization compared with no revascularization for comparable CFC severity. Non-severe CFC showed no benefit. Discordance between observed actual and virtual hypothetical post-revascularization survival probability revealed residual CAD or failed revascularization.

An Echogenic Clot Method for Thrombolysis Monitoring in Thrombotic Stroke Models.

To demonstrate thrombolytic efficacy of a tissue plasminogen activator (tPA)-loaded echogenic liposome (TELIP) formulation in a rabbit thrombotic stroke model (the most relevant animal model for evaluation of directed thrombolytic therapy for ischemic stroke), we sought to develop a means of monitoring thrombus dissolution quantitatively by ultrasound imaging methods. We hypothesized that a gas-free ultrasound contrast agent can be incorporated into blood clots at a concentration that does not affect the tPA-mediated clot dissolution rate, while enabling quantitative assessment of the clot dissolution rate. Clots were formed from a mixture of whole rabbit blood, 1 M calcium chloride, human thrombin and varying amounts of microcrystalline cellulose. Washed clots in tubes were weighed at 30, 60 and 90 minutes after addition of recombinant tPA (rtPA) in porcine plasma (100 µg/ml). Clot echogenicity at each time point was assessed using a Philips HDI 5000 ultrasound system using an L12-5 linear array probe. Recorded Images underwent videodensitometric analysis that converted image reflectivity to mean gray scale values (MGSV). We found that 1.12 mg/ml of microcrystalline cellulose in rabbit blood clots (0.2 ml) provided optimal echogenicity without affecting clot dissolution rates (0.3-0.6 mg/min.) caused by rtPA. The clot dissolution rate measured by videodensitometric analysis of the echogenic clots agreed well with that determined by mass loss measurements (0.28% 0-time value/minute). This method will be important for demonstrating in vivo efficacy with potentially decreased hemorrhagic effects provided by directed tPA vehicles relative to systemic administration of the free thrombolytic.

A Two-Step Transcriptome Analysis of the Human Heart Reveals Broad and Disease-Responsive Expression of Ectopic Olfactory Receptors.

G-protein-coupled receptors (GPCRs) are critical regulators of cardiac physiology and a key therapeutic target for the treatment of heart disease. Ectopic olfactory receptors (ORs) are GPCRs expressed in extra-nasal tissues which have recently emerged as new mediators in the metabolic control of cardiac function. The goals of this study were to profile OR gene expression in the human heart, to identify ORs dysregulated by heart failure caused by ischemic cardiomyopathy, and to provide evidence suggestive of a role for those altered ORs in the pathogenesis of heart failure. Left ventricular tissue from heart failure patients (n = 18) and non-failing heart samples (n = 4) were subjected to a two-step transcriptome analysis consisting of the quantification of 372 distinct OR transcripts on real-time PCR arrays and simultaneous determination of global cardiac gene expression by RNA sequencing. This strategy led to the identification of >160 ORs expressed in the human heart, including 38 receptors differentially regulated with heart failure. Co-expression analyses predicted the involvement of dysregulated ORs in the alteration of mitochondrial function, extracellular matrix remodeling, and inflammation. We provide this dataset as a resource for investigating roles of ORs in the human heart, with the hope that it will assist in the identification of new therapeutic targets for the treatment of heart failure.

Storage Stability of Atheroglitatide, an Echogenic Liposomal Formulation of Pioglitazone Targeted to Advanced Atheroma with a Fibrin-Binding Peptide.

We have conducted a stability study of a complex liposomal pharmaceutical product, Atheroglitatide (AGT), stored at three temperatures, 4, 24, and 37 °C, for up to six months. The six parameters measured were functions of liposomal integrity (size and number), drug payload (loading efficiency), targeting peptide integrity (conjugation efficiency and specific avidity), and echogenicity (ultrasound-dependent controlled drug release), which were considered most relevant to the product's intended use. At 4 °C, liposome diameter trended upward, indicative of aggregation, while liposome number per mg lipid and echogenicity trended downward. At 24 °C, peptide conjugation efficiency (CE) and targeting efficiency (TE, specific avidity) trended downward. At 37 °C, CE and drug (pioglitazone) loading efficiency trended downward. At 4 °C, the intended storage temperature, echogenicity, and liposome size reached their practical tolerance limits at 6 months, fixing the product expiration at that point. Arrhenius analysis of targeting peptide CE and drug loading efficiency decay at the higher temperatures indicated complete stability of these characteristics at 4 °C. The results of this study underscore the storage stability challenges presented by complex nanopharmaceutical formulations.

Enhanced Cerebroprotection of Xenon-Loaded Liposomes in Combination with rtPA Thrombolysis for Embolic Ischemic Stroke.

Xenon (Xe) has shown great potential as a stroke treatment due to its exceptional ability to protect brain tissue without inducing side effects. We have previously developed Xe-loaded liposomes for the ultrasound-activated delivery of Xe into the cerebral region and demonstrated their therapeutic efficacy. At present, the sole FDA-approved thrombolytic agent for stroke treatment is recombinant tissue plasminogen activator (rtPA). In this study, we aimed to investigate the potential of combining Xe-liposomes with an intravenous rtPA treatment in a clinically relevant embolic rat stroke model. We evaluated the combinational effect using an in vitro clot lysis model and an in vivo embolic middle cerebral artery occlusion (eMCAO) rat model. The treatment groups received intravenous administration of Xe-liposomes (20 mg/kg) at 2 h post-stroke onset, followed by the administration of rtPA (10 mg/kg) at either 2 or 4 h after the onset. Three days after the stroke, behavioral tests were conducted, and brain sections were collected for triphenyltetrazolium chloride (TTC) and TUNEL staining. Infarct size was determined as normalized infarct volume (%). Both in vitro and in vivo clot lysis experiments demonstrated that Xe-liposomes in combination with rtPA resulted in effective clot lysis comparable to the treatment with free rtPA alone. Animals treated with Xe-liposomes in combination with rtPA showed reduced TUNEL-positive cells and demonstrated improved neurological recovery. Importantly, Xe-liposomes in combination with late rtPA treatment reduced rtPA-induced hemorrhage, attributing to the reduction of MMP9 immunoreactivity. This study demonstrates that the combined therapy of Xe-liposomes and rtPA provides enhanced therapeutic efficacy, leading to decreased neuronal cell death and a potential to mitigate hemorrhagic side effects associated with late rtPA treatment.

Liposome-Based Carriers for CRISPR Genome Editing.

The CRISPR-based genome editing technology, known as clustered regularly interspaced short palindromic repeats (CRISPR), has sparked renewed interest in gene therapy. This interest is accompanied by the development of single-guide RNAs (sgRNAs), which enable the introduction of desired genetic modifications at the targeted site when used alongside the CRISPR components. However, the efficient delivery of CRISPR/Cas remains a challenge. Successful gene editing relies on the development of a delivery strategy that can effectively deliver the CRISPR cargo to the target site. To overcome this obstacle, researchers have extensively explored non-viral, viral, and physical methods for targeted delivery of CRISPR/Cas9 and a guide RNA (gRNA) into cells and tissues. Among those methods, liposomes offer a promising approach to enhance the delivery of CRISPR/Cas and gRNA. Liposomes facilitate endosomal escape and leverage various stimuli such as light, pH, ultrasound, and environmental cues to provide both spatial and temporal control of cargo release. Thus, the combination of the CRISPR-based system with liposome delivery technology enables precise and efficient genetic modifications in cells and tissues. This approach has numerous applications in basic research, biotechnology, and therapeutic interventions. For instance, it can be employed to correct genetic mutations associated with inherited diseases and other disorders or to modify immune cells to enhance their disease-fighting capabilities. In summary, liposome-based CRISPR genome editing provides a valuable tool for achieving precise and efficient genetic modifications. This review discusses future directions and opportunities to further advance this rapidly evolving field.

Endothelial Dysfunction and Cardiometabolic Risk Factors in Mexican American Adults: The Cameron County Hispanic Cohort.

Endothelial dysfunction assessed by impaired brachial flow-mediated dilation (FMD) predicts incident cardiovascular disease (CVD). We have previously shown that clustering of diabetes mellitus, obesity, and metabolic syndrome in young Hispanic patients was associated with subclinical atherosclerosis. This study aimed to assess determinants of impaired FMD response (%FMD), an earlier marker of atherosclerosis, in a population-based sample of asymptomatic Mexican Americans. Cardiometabolic biomarkers and FMD were obtained from 960 Cameron County Hispanic Cohort participants. Gender-specific median values of %FMD were used to categorize participants into those with %FMD below or above the median. The sample was further stratified into those younger and older than 55 years. Survey-weighted logistic regression analyses were conducted to evaluate the effects of cardiometabolic biomarkers on the %FMD groups. The low %FMD group was significantly older, had higher visceral adipose tissue, systolic blood pressure, or plasma glucose, and had metabolic syndrome compared with those in the high %FMD group. Multivariable-adjusted age-stratified logistic regression analyses showed that in older participants, male gender (odds ratio [OR] = 2.4 [1.4 to 4.2]) and having hypertension (OR = 2.3 [1.3 to 4.3]) or prediabetes mellitus (OR = 3.4 [1.5 to 7.5]) remained significantly associated with odds of low %FMD. In younger participants, high low-density lipoprotein (OR = 2.8 [1.6 to 4.9]) or having the metabolic syndrome (OR = 1.9 [1.1 to 3.6]) were significantly associated with odds of low %FMD. In conclusion, we found age-dependent associations between cardiometabolic biomarkers and an FMD response below the gender-specific median in a sample composed of Mexican Americans without previous CVD. Targeting specific risk factors by age may mitigate progression to incident CVD in this high-risk racial disparity group.

Co-Delivery of Therapeutics and Bioactive Gas Using a Novel Liposomal Platform for Enhanced Treatment of Acute Arterial Injury.

Atherosclerosis is a complex, multi-stage disease characterized by pathological changes across the vascular wall. Endothelial dysfunction, inflammation, hypoxia, and vascular smooth muscle cell proliferation contribute to its progression. An effective strategy capable of delivering pleiotropic treatment to the vascular wall is essential to limit neointimal formation. Echogenic liposomes (ELIP), which can encapsulate bioactive gases and therapeutic agents, have the potential to deliver enhanced penetration and treatment efficacy for atherosclerosis. In this study, liposomes loaded with nitric oxide (NO) and rosiglitazone, a peroxisome proliferator-activated receptor agonist, were prepared using hydration, sonication, freeze-thawing, and pressurization. The efficacy of this delivery system was evaluated in a rabbit model of acute arterial injury induced by balloon injury to the common carotid artery. Intra-arterial administration of rosiglitazone/NO co-encapsulated liposomes (R/NO-ELIP) immediately following injury resulted in reduced intimal thickening after 14 days. The anti-inflammatory and anti-proliferative effects of the co-delivery system were investigated. These liposomes were echogenic, enabling ultrasound imaging to assess their distribution and delivery. R/NO-ELIP delivery exhibited a greater attenuation (88 ± 15%) of intimal proliferation when compared to NO-ELIP (75 ± 13%) or R-ELIP (51 ± 6%) delivery alone. The study demonstrates the potential of echogenic liposomes as a promising platform for ultrasound imaging and therapeutic delivery.

Initiating and imaging cavitation from infused echo contrast agents through the EkoSonic catheter.

Ultrasound-enhanced delivery of therapeutic-loaded echogenic liposomes is under development for vascular applications using the EkoSonic Endovascular System. In this study, fibrin-targeted echogenic liposomes loaded with an anti-inflammatory agent were characterized before and after infusion through an EkoSonic catheter. Cavitation activity was nucleated by Definity or fibrin-targeted, drug-loaded echogenic liposomes infused and insonified with EkoSonic catheters. Passive cavitation imaging was used to quantify and map bubble activity in a flow phantom mimicking porcine arterial flow. Cavitation was sustained during 3-min infusions of Definity or echogenic liposomes along the distal 6 cm treatment zone of the catheter. Though the EkoSonic catheter was not designed specifically for cavitation nucleation, infusion of drug-loaded echogenic liposomes can be employed to trigger and sustain bubble activity for enhanced intravascular drug delivery.

Demonstration of ultrasound-mediated therapeutic delivery of fibrin-targeted pioglitazone-loaded echogenic liposomes into the arterial bed for attenuation of peri-stent restenosis.

Peri-stent restenosis following stent implantation is a major clinical problem. We have previously demonstrated that ultrasound-facilitated liposomal delivery of pioglitazone (PGN) to the arterial wall attenuated in-stent restenosis. To evaluate ultrasound mediated arterial delivery, in Yucatan miniswine, balloon inflations were performed in the carotid and subclavian arteries to simulate stent implantation and induce fibrin formation. The fibrin-binding peptide, GPRPPGGGC, was conjugated to echogenic liposomes (ELIP) containing dinitrophenyl-L-alanine-labelled pioglitazone (DNP-PGN) for targeting purposes. After pre-treating the arteries with nitroglycerine, fibrin-binding peptide-conjugated PGN-loaded ELIP (PAFb-DNP-PGN-ELIP also termed atheroglitatide) were delivered to the injured arteries via an endovascular catheter with an ultrasound core, either with or without ultrasound application (EKOSTM Endovascular System, Boston Scientific). In arteries treated with atheroglitatide, there was substantial delivery of PGN into the superficial layers (5 µm from the lumen) of the arteries with and without ultrasound, [(1951.17 relative fluorescence units (RFU) vs. 1901.17 RFU; P-value = 0.939)]. With ultrasound activation there was increased penetration of PGN into the deeper arterial layers (up to 35 µm from the lumen) [(13195.25 RFU vs. 7681.00 RFU; P-value = 0.005)]. These pre-clinical data demonstrate ultrasound mediated therapeutic vascular delivery to deeper layers of the injured arterial wall. This model has the potential to reduce peri- stent restenosis.

Assessment of bubble activity generated by histotripsy combined with echogenic liposomes.

Objective.Histotripsy is a form of focused ultrasound therapy that uses the mechanical activity of bubbles to ablate tissue. While histotripsy alone degrades the cellular content of tissue, recent studies have demonstrated it effectively disrupts the extracellular structure of pathologic conditions such as venous thrombosis when combined with a thrombolytic drug. Rather than relying on standard administration methods, associating thrombolytic drugs with an ultrasound-triggered echogenic liposome vesicle will enable targeted, systemic drug delivery. To date, histotripsy has primarily relied on nano-nuclei inherent to the medium for bubble cloud generation, and microbubbles associated with echogenic liposomes may alter the histotripsy bubble dynamics. The objective of this work was to investigate the interaction of histotripsy pulse with echogenic liposomes.Approach.Bubble clouds were generated using a focused source in anin vitromodel of venous flow. Acoustic emissions generated during the insonation were passively acquired to assess the mechanical activity of the bubble cloud. High frame rate, pulse inversion imaging was used to track the change in echogenicity of the liposomes following histotripsy exposure.Main results.For peak negative pressures less than 20 MPa, acoustic emissions indicative of stable and inertial bubble activity were observed. As the peak negative pressure of the histotripsy excitation increased, harmonics of the excitation were observed in OFP t-ELIP solutions and plasma alone. Additional observations with high frame rate imaging indicated a transition of bubble behavior as the pulse pressure transitioned to shock wave formation.Significance.These observations suggest that a complex interaction between histotripsy pulses and echogenic liposomes that may be exploited for combination treatment approaches.

Improving transcatheter aortic valve interventional predictability via fluid-structure interaction modelling using patient-specific anatomy.

Transcatheter aortic valve replacement (TAVR) is now a standard treatment for high-surgical-risk patients with severe aortic valve stenosis. TAVR is being explored for broader indications including degenerated bioprosthetic valves, bicuspid valves and for aortic valve (AV) insufficiency. It is, however, challenging to predict whether the chosen valve size, design or its orientation would produce the most-optimal haemodynamics in the patient. Here, we present a novel patient-specific evaluation framework to realistically predict the patient's AV performance with a high-fidelity fluid-structure interaction analysis that included the patient's left ventricle and ascending aorta (AAo). We retrospectively evaluated the pre- and post-TAVR dynamics of a patient who underwent a 23 mm TAVR and evaluated against the patient's virtually de-calcified AV serving as a hypothetical benchmark. Our model predictions were consistent with clinical data. Stenosed AV produced a turbulent flow during peak-systole, while aortic flow with TAVR and de-calcified AV were both in the laminar-to-turbulent transitional regime with an estimated fivefold reduction in viscous dissipation. For TAVR, dissipation was highest during early systole when valve deformation was the greatest, suggesting that an efficient valve opening may reduce energy loss. Our study demonstrates that such patient-specific modelling frameworks can be used to improve predictability and in the planning of AV interventions.

The CTSA University of Texas Health Science Center (UTHSC) Northeast-Tyler and Rio Grande Valley Success Story: How Rural, Underserved Academic Communities Rapidly Built a Robust Engine for Collaborative COVID-19 Clinical Research.

In 2018, The University of Texas Health Science Center-Tyler and University of Texas Rio Grande Valley were invited to develop clinical research units for an existing Clinical and Translational Science Award (CTSA) consortium with the objective to equip medically underserved, economically disadvantaged communities and subsequently to deploy COVID-19 clinical trials in response to a public health emergency.

Repetitive xenon treatment improves post-stroke sensorimotor and neuropsychiatric dysfunction.

Stroke is a life-changing event as stroke survivors experience changes in personality, emotions and mood. We investigated the effect of xenon gas encapsulated in liposomes on stroke-generated sensorimotor impairments, and anxiety- and depression-like phenotypes. Ischemic stroke was created by the intraluminal middle cerebral artery occlusion (MCAO) for 6 h followed by reperfusion in rats. Xenon-liposome (6 mg/kg, intravenous) treatment was given multiple times starting at 2 h post-ischemia through 6 h (5X), and once-daily for next 3 days. Rats underwent ischemic injury displayed sensorimotor deficits in the adhesive removal, vibrissae-evoked forelimb placement and rotarod tests. These animals also made lesser entries and spent less time on open arms of the elevated-plus maze and swam more in passive mode in the forced swimming test, indicating anxiety- and depression-like behaviors at 28- and 35-days post-injury, respectively. Repeated intravenous treatment with xenon-liposomes ameliorated these behavioral aberrations (p < 0.05). Gut microbiome analysis (16S ribosomal-RNA gene sequencing) showed a decrease in the Clostridium clusters XI, XIVa, XVIII and Lactobacillus bacterium, and increase of the Prevotella in the xenon-liposome group. No microbiota communities were majorly affected across the treatments. Moreover, xenon treatment group showed augmented plasma levels of IL-6 cytokines (∼5 fold) on day-35 post-ischemia, while no change was noticed in the IL-1ß, IL-4, IL-10, IL-13 and MCP-1 levels. Our data highlights the safety, behavioral recovery and reversal of post-stroke brain injury following xenon-liposome treatment in an extended ischemic model. These results show the potential for this treatment strategy to be translated to patients with stroke.