Compositions and Methods for Enhanced Mitochondrial Delivery for Regenerative Therapies

SHORT DESCRIPTION
A novel peptide coating process that improves mitochondrial cell uptake, preserves function, and enables targeted delivery for cardiovascular and regenerative therapies.

NU Tech ID

NU 2025-055

INVENTORS

• Bin Jiang*
  • Northwestern University Feinberg School of Medicine, Department of Surgery (Vascular Surgery Division)
• Brandon Applewhite

IP STATUS

US Patent Pending

DEVELOPMENT STAGE

Target Validation

• Cell-based readouts

BACKGROUND
Mitochondria, the powerhouse of eukaryotic cells, are responsible for many essential cellular functions, including energy metabolism, calcium homeostasis, cell survival, differentiation, and death. Dysfunctional mitochondria contribute to a wide range of diseases, including cardiovascular diseases (CVDs), neurodegenerative disorders, metabolic syndromes, and aging-related conditions. Therapeutic strategies aimed at restoring mitochondrial function hold immense potential across multiple biomedical fields. Mitochondrial transplantation has emerged as a potential regenerative strategy for rejuvenating damaged cells and tissues, with various studies demonstrating that exogenous mitochondria can integrate into recipient cells, restore bioenergetic function, reduce oxidative stress, and improve survival. However, loss of function and viability after isolation, efficient delivery, and ensuring targeted uptake by specific cell types remain a challenge, with existing methods incurring high costs and lacking delivery specificity. New strategies to overcome these limitations in delivering mitochondria to cells for use in managing and treating disorders and diseases are needed.

ABSTRACT
This invention presents a method for coating mitochondria with targeting peptides using DSPE-PEG polymers to enable controlled transplantation. The modification improves mitochondrial viability, maintains mitochondrial function, boosts cell uptake, and enables targeted delivery. Early in vitro data demonstrate mitochondria functionalized with DSPE-PEG conjugated to peptides targeting VCAM-1, an inflammatory adhesion molecule upregulated in chronic vascular diseases, and collagen IV, a subendothelial matrix protein exposed upon endothelial injury, significantly enhanced mitochondrial uptake in diabetic aortic endothelial cells (DAECs), which exhibit baseline mitochondrial dysfunction due to their diabetic origin, compared to uncoated mitochondria. Further assessments demonstrated increased cytoplasmic retention and greater colocalization with the endogenous mitochondrial network, improved mitochondrial membrane potential, and sustained oxygen consumption in recipient cells. This proof-of-concept demonstrates mitochondria surface engineering can enhance mitochondria transplantation, resulting in improved cellular uptake and bioenergetic restoration in damaged endothelium, thus addressing the current challenges in mitochondrial therapies, and lays the foundation for precision mitochondrial delivery technologies with therapeutic potential across a wide range of indications.

APPLICATIONS

• Treatment of vascular diseases and endothelial dysfunction
• Cardiovascular therapies for myocardial infarction and vascular repair
• Enhancing cell-based therapy outcomes with improved mitochondrial function.
• ​​​​​​Potential applications in neurodegenerative diseases, cancer, and inflammation
• Research tools: Providing a platform to study mitochondrial behavior in cellular therapies.

ADVANTAGES

• Enhances cell uptake: Boosts mitochondrial entry into target cells.
• Preserves function: Maintains mitochondrial integrity post-isolation.
• Enables targeted delivery: Facilitates tissue and cell-specific transplantation.
• Improves therapeutic efficiency: Increases overall efficacy in cardiovascular and regenerative medicine applications.
• Utilizes a simple, biocompatible coating process with unique polymers not previously applied in this context.
• Makes mitochondria therapies more effective, predictable, and controllable.

PUBLICATIONS

• Applewhite, B. et al., Surface-Engineered Mitochondria with Targeting Potential for Endothelial Repair. Cel. Mol. Bioeng. Aug 22, 2025.
• Matiuto, N. et al., Harnessing Mitochondrial Transplantation to Target Vascular Inflammation in Cardiovascular Health. JACC Basic Transl Sci. Aug, 2025.

KEYWORDS
Mitochondrial dysfunction, mitochondrial delivery, mitochondrial transplantation, bioenergetics, oxidative stress, targeted delivery, cardiovascular therapy, vascular disease, regenerative medicine