Researchers have developed a novel lipid nanoparticle capable of delivering therapeutic messenger RNA (mRNA) directly into the dense, complex tissue of heart muscle cells. This breakthrough, achieved using a sophisticated “heart-on-a-chip” model, overcomes a significant hurdle that has long stalled the advancement of genetic therapies for cardiovascular disease, potentially paving the way for new treatments that can repair cellular damage after a heart attack or correct genetic defects.
The new delivery system addresses a critical challenge in cardiac medicine: efficiently getting therapeutic agents through the tough environment of heart tissue and into the target cells, known as cardiomyocytes. By engineering a nanoparticle with a unique, acid-degradable coating, a team led by University of California, Berkeley, researchers created a vehicle that can not only penetrate the tissue but also escape a cellular trap that degrades most treatments before they can work. The success of this method in both lab models and animal studies opens the door to a new class of therapies for heart failure, the leading cause of death worldwide.
Miniaturized Human Heart Models Drive Discovery
At the core of the research was a human cardiac microphysiological system (MPS), a device commonly called a heart-on-a-chip. This platform provides a miniaturized, functional model of the human heart, featuring microfluidic channels lined with living human cells that form three-dimensional micromuscles. This advanced model allows scientists to mimic the physiological environment of the heart, including its dense tissue and the mechanical forces at play, offering a far more accurate testing ground than traditional 2D models where cells are grown in a flat layer on a petri dish.
The research team, which also included members from the Gladstone Institutes and UC San Francisco, leveraged the heart-on-a-chip to test various formulations of lipid nanoparticles. LNPs are tiny, fat-based spheres that encapsulate therapeutic agents and are considered the most clinically advanced non-viral system for delivering mRNA, famously used in the Pfizer-BioNTech and Moderna COVID-19 vaccines. By observing how different LNP designs interacted with the 3D heart tissue on the chip, the scientists could rapidly identify the most effective candidate for penetrating the tissue and delivering its genetic payload into the cardiomyocytes.
Breaking Through the Cellular Wall
A primary obstacle to delivering mRNA to heart muscle cells is a biological process known as endosomal escape. After an LNP is absorbed by a cell, it is enclosed within a bubble-like compartment called an endosome. This endosome acts as a sorting station, and if the therapeutic agent gets stuck there, the cell’s natural processes will begin to break it down, rendering the treatment useless. For a therapy to be effective, the nanoparticle must break out of the endosome and enter the cell’s main interior, the cytoplasm, where it can release its mRNA cargo to be translated into therapeutic proteins.
To solve this long-standing delivery problem, the researchers synthesized LNPs with a novel acid-degradable polyethylene glycol coating. The unique properties of this coating serve a dual purpose. First, it helps the nanoparticle diffuse through the crowded and dense heart tissue to reach the cells. Second, once inside the acidic environment of the endosome, the coating is designed to degrade, which facilitates the nanoparticle’s escape into the cytoplasm. This innovative design ensures the mRNA payload arrives intact at its destination, ready to perform its therapeutic function.
From Lab Model to Living Organisms
After identifying the most promising LNP formulation using the heart-on-a-chip, the researchers moved to validate their findings in a living organism. They tested the optimized nanoparticles on mouse hearts and observed similar, positive results, confirming that the LNPs could efficiently deliver their cargo to cardiomyocytes in a complex animal model. This crucial step demonstrated that the discoveries made on the miniaturized lab model could be successfully translated to a biological system.
This approach aligns with broader research efforts that have established proof of concept for LNP-mediated mRNA delivery in larger animal models, including pigs, for cardiac tissue regeneration. The ability to test and refine these delivery systems on a chip first can significantly reduce the time, cost, and number of animals required for research. According to Kevin Healy, a co-principal investigator of the study and a Berkeley professor of bioengineering, this framework enables “faster, animal-sparing identification of effective lipid nanoparticles for safely delivering these therapies.”
The Future of Cardiac Therapeutics
The successful delivery of mRNA to heart muscle cells has profound implications for treating a range of cardiovascular diseases. One of the most promising applications is in repairing the heart after a myocardial infarction, or heart attack. By delivering mRNA that codes for regenerative proteins, it may be possible to trigger the body’s own repair mechanisms to heal damaged tissue. Researchers are also exploring how this technology could be used to deliver gene-correction therapies for inherited heart conditions. For the millions of patients suffering from heart failure, this work represents a significant step toward developing novel and more effective treatments.
Professor Healy noted that by using organ-on-a-chip models to predict heart-targeted delivery and safety, scientists can potentially accelerate programs for heart failure therapeutics and cardioprotective factors. This method streamlines the early phases of drug discovery and development, allowing for more rapid translation of promising therapies from the lab to clinical trials.
Challenges in Targeted Delivery
While direct injection into the heart muscle, known as intramyocardial administration, is effective for localized treatment, a key challenge remains for systemic therapies that would be administered intravenously. When LNPs are injected into the bloodstream, they have a strong tendency to accumulate in other organs, particularly the liver and spleen. This off-target delivery reduces the amount of the therapeutic agent that reaches the heart and can cause unwanted side effects. Researchers are actively working on improving the “tropism,” or tissue-specificity, of LNPs to ensure more of the cargo reaches the intended cardiac tissue.
Other research is exploring alternative delivery vehicles to overcome this limitation. One promising approach involves using extracellular vesicles (EVs), which are naturally occurring nanoparticles that cells use to communicate with each other. Studies have shown that EVs derived from cardiac progenitor cells are more efficient at targeting the heart and result in minimal liver accumulation compared to conventional LNPs when administered systemically in mice. Improving precision targeting remains a critical focus as scientists work to optimize these powerful new delivery systems for safe and effective clinical use.