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  • Review Article
  • Published:

Targeted delivery of therapeutic agents to the heart

Nature Reviews Cardiology volume 18, pages 389–399 (2021)Cite this article

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Abstract

For therapeutic materials to be successfully delivered to the heart, several barriers need to be overcome, including the anatomical challenges of access, the mechanical force of the blood flow, the endothelial barrier, the cellular barrier and the immune response. Various vectors and delivery methods have been proposed to improve the cardiac-specific uptake of materials to modify gene expression. Viral and non-viral vectors are widely used to deliver genetic materials, but each has its respective advantages and shortcomings. Adeno-associated viruses have emerged as one of the best tools for heart-targeted gene delivery. In addition, extracellular vesicles, including exosomes, which are secreted by most cell types, have gained popularity for drug delivery to several organs, including the heart. Accumulating evidence suggests that extracellular vesicles can carry and transfer functional proteins and genetic materials into target cells and might be an attractive option for heart-targeted delivery. Extracellular vesicles or artificial carriers of non-viral and viral vectors can be bioengineered with immune-evasive and cardiotropic properties. In this Review, we discuss the latest strategies for targeting and delivering therapeutic materials to the heart and how the knowledge of different vectors and delivery methods could successfully translate cardiac gene therapy into the clinical setting.

Key points

  • Therapies directed at modifying gene expression are emerging and have shown positive results for non-cardiac diseases in clinical trials; clinical translation of these therapies for cardiac diseases remains slow.

  • Currently, cardiac-specific delivery of therapeutic materials in large mammals requires invasive approaches, and the patterns of distribution depend on the delivery method used.

  • Vector options for gene delivery are increasing; adeno-associated viruses provide safe gene delivery but their gene-transduction efficacy in the human heart remains suboptimal.

  • Extracellular vesicles hold immense potential for the delivery of therapeutic agents; their clinical applications depend on their efficient isolation, scalability, drug loading, biodistribution and tissue targeting.

  • Next-generation cardiovascular therapeutics might include bioengineered macromolecules, viruses, nanobiologics and extracellular vesicles.

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Fig. 1: Exosomes can envelope AAV vectors to shield them from neutralizing antibodies.
Fig. 2: Delivery methods targeting the heart.
Fig. 3: Factors that influence cardiac uptake of therapeutic agents.

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Acknowledgements

The authors are supported by grants NIH R01HL140469, R01HL124187 and R01HL148786 and New York Stem Cell Science (NYSTEM) C32562GG to S.S., and NIH R01HL139963 and AHA-SDG 17SDG33410873 to K.I. The authors acknowledge the Gene Therapy Resource Program (GTRP) of the National Heart, Lung, and Blood Institute.

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  1. Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Susmita Sahoo, Taro Kariya & Kiyotake Ishikawa

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  1. Susmita Sahoo
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  2. Taro Kariya
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  3. Kiyotake Ishikawa
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The authors contributed equally to all aspects of the article.

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Glossary

Polyplex particles

Any complex of a polymer and a nucleic acid (DNA or RNA interference molecules) formed through electrostatic interactions between cationic groups of the polymer and the negatively charged nucleic acids.

Episome

A segment of DNA that exists independently of a chromosome.

Second-strand synthesis

DNA synthesis to form double-stranded DNA after delivery of single-stranded DNA.

Zeta potential

A measure of the effective electric charge on the surface of an extracellular vesicle (EV) (or nanoparticle); the potential is calculated by quantifying the electrophoretic mobility of EVs in liquid between electrodes when a field is applied.

Retroperfusion

Injection through the coronary sinus (vein).

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Sahoo, S., Kariya, T. & Ishikawa, K. Targeted delivery of therapeutic agents to the heart. Nat Rev Cardiol 18, 389–399 (2021). https://doi.org/10.1038/s41569-020-00499-9

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