Targeted Mitochondrial Delivery Systems for Vascular Interventions

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PROJECT SUMMARY Mitochondrial dysfunction is a significant contributing factor in many common disorders, yet no pharmacological treatment is currently available to restore mitochondrial function. An emerging therapeutic strategy is intercellular mitochondrial transfer, where healthy mitochondria from a donor cell source can be transported to the stressed recipient cells to achieve functional restoration. However, this strategy is currently hindered by several significant technological challenges, including the lack of cell/tissue specificity, low cell internalization rate, and loss of mitochondria function during delivery. Therefore, engineering targeted delivery systems to facilitate cell-specific internalization with functional preservation is important for the clinical adaptation of the technology. The long- term goal is to develop mitochondria-based therapeutics for common diseases in which mitochondrial dysfunction is a prominent feature. The objective of this project is to develop advanced Mitochondrial Delivery Systems (MDS) with high specificity, high efficiency, and functional preservation to enable control over the quantity and quality of the transferred mitochondria. To achieve this goal, rational biomaterial design will be utilized to enable the efficient delivery of mitochondria in three types of configurations, each designed to account for differences in tissue accessibility and target-cell properties in the vascular system. Specifically, an intravascular MDS will be developed to target dysfunctional endothelium (Aim 1), an endovascular MDS will be developed to target apoptotic vascular smooth muscle cells (Aim 2), and a perivascular MDS will be developed to target proinflammatory macrophages (Aim 3). The MDS will be engineered to achieve localization and internalization to the target cell types, with functional preservation for mitochondria as the cargo for delivery. The MDS will be firstly optimized for each of the target cell types in vitro, followed by validation of the delivery technology and therapeutic potential in vivo. Through this work, we are expected to establish several clinical applicable delivery tools that can effectively deliver functional mitochondria to diseased tissues. This study will also provide key technological advancements toward developing mitochondria-based therapeutics for vascular interventions, which may significantly expand the therapeutic options for various cardiovascular disease patients. This technology will be designed to be modifiable/customizable for other diseases and cell types where mitochondrial dysfunction is involved, thus leading to a series of innovative devices and therapeutics for more efficacious treatments for many common pathologies involving dysfunctional mitochondria.