Translational Mitochondrial Therapeutics for Endothelial Repair in Vascular Surgery

About This Grant

Project Summary/Abstract Despite surgical advancement and endovascular device innovations, endothelial injury remains a fundamental barrier in vascular surgeries, contributing to post-operative complications such as vein graft failure, restenosis, and thrombosis. Current surgical approaches offer no regenerative solution to actively protect endothelial health during or after interventions. To address this gap, we have developed a bioengineered mitochondrial therapy platform that leverages lipid-polymer-peptide surface functionalization to enable targeted mitochondria delivery, enhanced cellular uptake, and integration into the host mitochondrial network. Mitochondrial dysfunction is a key driver of impaired endothelial repair following vascular surgeries, yet mitochondrial transplantation has not been adopted clinically due to challenges in storage stability, scalability, and compatibility with surgical workflows. Our preliminary studies demonstrate successful surface engineering of stem cell–derived mitochondria with robust uptake and functional rescue in dysfunctional endothelial cells. In vivo, we show that engineered mitochondria were selectively uptake by target vessels during both intra-operative (ex vivo vein graft storage and arterial intraluminal infusion) and post-operative stages (intravenous injection) upon vascular surgeries. To further establish the translational potential of bioengineered mitochondrial therapy, we propose the following studies. Aim 1 will optimize mitochondrial source selection, storage formulation, and surface modification parameters to ensure translational feasibility. Aim 2 will validate the therapeutic efficacy and biodistribution of the optimized system in two highly clinically relevant in vivo models of open (vein graft bypass) and endovascular surgeries (balloon angioplasty). This interdisciplinary project integrates surgical sciences, bioengineering, translational medicine, and device development to establish a next-generation therapeutic approach for vascular surgeries. By advancing a procedural-compatible, device-enabled delivery system, this work directly addresses a critical need in vascular surgery by developing translatable tools and technologies to improve surgical outcomes in millions of patients with cardiovascular diseases.