Multi-functional magnetic nanorods for constructing theranostic extracellular vesicles for treating myocardial infarction

PROJECT SUMMARY Cardiovascular disease (CVD) remains the leading cause of death and a global public health burden. Myocardial injury with infarction (MI) is a common CVD that is associated with heart failure and even death. Cell-, especially stem cell (SC)-based therapies has been of great interest for treating heart diseases, because 1) the adult heart has a limited number of SCs and thus limited capacity of self-repair and regeneration, and 2) current treatment strategies are only able to limit the ensuing adverse dilatation and impaired contractile function. However, clinical translation of SC-based therapies remains cumbersome with very few successes, in a large part due to the safety and ethical concerns over uncontrollable differentiation of injected cells in patients. As mounting evidence reveals the SC-induced repairing functions predominately derived from the paracrine effect mediated by extracellular vesicles (EVs), therapies based on SC-derived EVs (SC-EVs) have emerged as a highly promising approach for cell-free regenerative medicine that delivers high potency but less side-effect associated with conventional cell-based therapy. A major limiting factor to the efficacy of EV-based treatment is the effectiveness of EV delivery to target tissues. Indeed, most animal studies employed direct cardiac injection in order to achieve significant treatment effects, although systemic administration is much preferred in the clinic. Moreover, clinical translation of new EV therapies requires non-invasive imaging for monitoring and quantification of EV delivery and treatment responses inpatients, which have not been fully developed yet. The overall goal of this STTR Phase I project takes an important first step to translate an MRI-guided, theranostic (therapeutics + diagnostics) EV platform developed in the research lab for effectively treating injured myocardium in acute MI. This collaborative project, between 5M Biomed and Kennedy Krieger Institute (KKI)/Johns Hopkins University (JHU), is built on our innovations in magnetic labeling and purification of therapeutic human SC-EVs, MRI-based EV tracking, and ultra-magnetic iron oxide nanorods (IONRs). We will focus on developing and validating a translatable theranostic EV system, using multifunctional ultra-magnetic IONRs that are suitable for efficient magnetic purification/enrichment, magnetic targeting, and non-invasive MRI of EVs. We will collaborate closely to 1) develop and optimize ultra-magnetic IONRs for efficient preparation of MagEV with high MRI contrast effect, and 2) test and validate the delivery and efficacy of MagEV labeled with IONRs in imaging and treating MI. The benchmark of success is to achieve an optimal formulation of MagEV, i.e., minimal interference of IONRs on MagEV functionalities and therapeutic potential together with high MRI capability and magnetism. The success of Phase I study will lead to the Phase II project, which will focus on scale-up manufacturing of MagEVs towards investigational new drug (IND) application and large-animal testing which will guide subsequent first-in-human studies.