Emerging nanotechnologies in cardiovascular medicine

Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide accounting for nearly 17.9 million deaths yearly.¹ CVDs encompass diseases of the conduit arteries (coronary, carotid, aorta and peripheral arteries, which may cause myocardial infarction, stroke, aneurysm or gangrene); the veins (which may result in venous ulcers and thromboembolism); the lymphatics (causing lymphedema); the microvasculature (associated with hypertension and vasculitis); the myocardium (precipitating heart failure and arrhythmias); and the valves and pericardium (which may also predispose to heart failure). Most CVD-associated deaths are linked to heart attacks and strokes and, while more common in individuals in the aging population, do not spare younger adults. Hypertension is another exceedingly prevalent condition and a major cause of premature death found to be directly linked to unhealthy diet, lack of physical activity, and obesity. Hypertension is expected to affect over 1.5 billion people worldwide by 2025.²

Part of the challenge in reducing mortality and suffering from CVD is that in many cases the CVD events are sudden acute events after long periods of clinically asymptomatic progression of disease which delays diagnosis and treatment. In the context of prevention and diagnosis, recent developments in machine learning, artificial intelligence (AI), wearable sensing electronics and big data analytics are poised to transform the management of CVD by making early diagnosis and treatment more accessible. Furthermore, these tools will enhance monitoring patients suffering from these conditions.^3–5 However, there is room to optimize treatment and to address the multifactorial mechanisms of CVD.⁶

Various therapeutic strategies are under development to tackle the unmet needs in the field. RNA-based therapeutics and regenerative medicine approaches are notable examples.^7,8 Expanding beyond the fields of infectious or neurodegenerative diseases and cancer, RNA therapeutics has significant promise in the treatment of CVDs⁹. Antisense oligonucleotides (ASO), small interfering RNAs (siRNAs), and microRNAs modulate gene expression and protein synthesis. Clinical trials are currently ongoing to assess the safety and efficacy of this class of drugs in the context of heart failure (NCT04045405), wound healing (NCT03603431), cardiac amyloidosis, atrial fibrillation, and hypercholesterolemia.¹⁰ More recently, a Phase II trial of VEGF mRNA for myocardial ischemia is under way. However, widespread development of RNA-based therapeutics has been limited by challenges such as molecular instability, poor tissue targeting and delivery, immunogenicity and adverse side effects.¹¹

Fortunately, nanotechnology offers solutions to address these limitations. Leveraging decades of effort in improving tissue targeting, therapeutic payload delivery and minimization of adverse effects for cancer, nanomedicine offers an arsenal of pharmaceutical platforms that have been leveraged for CVD^12–14 (Figure 1): liposomes, nanoparticles generated from reconstituted high density lipoprotein, amphiphilic block co-polymers and macromolecules, polyethylene glycol-polyethyleneimine, and dendrimers are only a few examples of nanoparticles developed for drug delivery.¹⁴ In this context, targeting specific tissues and inflammation in the cardiovascular network,¹⁵ stabilizing mRNA therapeutics, prolonging drug circulation time while reducing off-target effects, and engineering immunological responses are primary objectives of these strategies.¹⁶

Figure 1.

Arsenal of nanomedicines under development for the treatment and management of cardiovascular diseases.

In notable examples, by leveraging lipidoid nanoparticle formulation, Turnbull et al demonstrated efficient delivery of mRNA to the myocardium in rodent and porcine models.¹⁷ Sixty (60)-fold higher mRNA levels were achieved in the heart for the nano formulated molecule compared to naked mRNA, with off-target expression in lung, liver and spleen less than 10% compared to expression in the heart. In another study, Singh et al showed that mRNA formulated into alginate-particles resulted in rapid protein expression in primary cardiomyocytes and targeted expression in rodent and porcine models of acute myocardial infarction.¹⁸ More broadly, thanks to nanoformulation there is broad applicability in tissue-specific gene editing with impact that extends beyond CVDs.¹⁹

Beyond RNA therapeutics, extracellular vesicles, nanovesicles naturally secreted by cells that can be engineered for multiple therapeutic purposes, have gained significant attention.²⁰ In a recent study, Gat et al showed that extracellular vesicles produced by human induced pluripotent stem-cell derived cardiomyocytes, endothelial cells and smooth muscle cells improved cardiac function in a porcine model of myocardial infarction comparable to transplantation of the same types of cells.²¹ In another study, Saha et al showed that extracellular vesicles derived from cardiac progenitor cells could support the recovery of ischemic myocardium.²² These studies highlighted the therapeutic potential of extracellular vesicles as acellular therapeutics and have promoted new developments in bioengineered mimetic immunomodulatory nanovesicles as reviewed in this special issue.²³ Other relevant examples of cardiovascular nanotechnologies include platelet-inspired nanocells for targeted heart repair after ischemia,²⁴ and calcium phosphate nanoparticles of R7W-MP, designed for delivery via inhalation, which rapidly improve cardiac function in a model of diabetic cardiomyopathy.²⁵ Furthermore, biomimetic lipid particles decorated with leukocyte membranes were shown to be able to preferentially target sites of vascular inflammation and deliver a therapeutic cargo.²⁶

Beyond nanoparticle-based therapeutics, other nanotechnology strategies are being developed to modulate timing of drug administration in the context of chronic conditions.²⁷ Among these are controllable nanofluidic drug delivery implants for hypertension which synchronize drug administration following the chronobiology of the condition,²⁸ cardiac microneedle patches,²⁹ anticoagulant-delivery polytetrafluoroethylene devices, and nanocoated drug-eluting stents.³⁰

These technologies exemplify the breath of research efforts in cardiovascular nanomedicine. With the field expanding rapidly, new investments are needed to promote innovative developments. Notably, National Institutes of Health (NIH) funding focused on addressing the burden of CVD is substantially lower compared to other biomedical areas, and is only about half of the funding for cancer.⁶ Private organizations, foundations and philanthropy have stepped up to support the efforts in CVD nanomedicine. Among these, the Kostas family has partnered with Houston Methodist and Northeastern University to create a program focused on the development and translation of innovative cardiovascular nanotechnologies. The program currently at its 5th year has provided support for various investigations ranging from nanodevices to RNA therapeutics and fostered multi-institutional and multidisciplinary collaboration among scientists from various institutions, through yearly symposia. This topical issue of Nanomedicine: Nanotechnology Biology and Medicine captures part of the multidisciplinary science and collaborative efforts supported by the Kostas program. The generous philanthropic support is essential for early proof of concept and exploratory studies, leading to mature funding proposals for the NIH, DOD and American Heart Association among others, establishing a model to foster innovative research in the field of Cardiovascular Nanomedicine that can become self-sustaining.

The convergence of innovative ideas stemming from different areas of science and the strong support from federal institutes, foundations, and visionary donors such as the Kostas family is essential to create a fertile environment for the development and testing of bold new concepts. This is welcome at a time where regulatory approvals of new cardiovascular therapeutics have progressively declined. Additionally, the multifaceted aspects of cardiovascular diseases call for personalized diagnostics and therapeutics to offer patients more effective alternatives to widespread and rudimentary one-size-fits-all approaches. The technologies and expertise to achieve this goal are readily available and breakthrough discoveries are just around the corner.