For a heart just damaged by a blocked artery, timing matters. So does access. That is what makes a new experimental treatment stand out: instead of being delivered directly to the heart, it is injected into muscle, where it coaxes the body to make a heart-protective hormone for weeks.
In a study published in Science, researchers reported that a single intramuscular injection helped mice and pigs recover after myocardial infarction, or heart attack. The treatment uses self-amplifying RNA packaged in lipid nanoparticles, a system designed to keep cells producing a therapeutic molecule longer than conventional mRNA can.
A hormone the injured heart already knows
The therapy centers on ANP, short for atrial natriuretic peptide, a hormone involved in cardiovascular homeostasis. After a heart attack, the body naturally raises ANP levels, but the adult heart does not appear to produce enough of it to drive strong repair.
Intramuscular injectable saNppa-LNP therapy for durable cardioprotection. (CREDIT: Science)
The researchers traced part of that idea to a striking contrast between newborn and adult mice. Three days after a heart attack, Nppa, the gene that encodes pro-ANP, rose about 10-fold in adult hearts but more than 25-fold in neonatal hearts. When the team knocked down Nppa in neonatal mice, heart function worsened. Left ventricular ejection fraction fell from about 60% to below 40%, and fibrosis increased.
That suggested ANP was not just present during recovery. It was doing useful work.
“It’s essentially a boost to the heart’s own defense system,” Huang said. “The body already uses ANP as a protective tool. We’re just helping it produce enough to matter during a critical window of healing.”
Why the injection lasts longer
The new treatment carries instructions for the Nppa gene in self-amplifying RNA, or saRNA. Unlike standard mRNA, saRNA can briefly copy itself inside cells, which extends how long the target protein is made. In this case, the RNA was packaged into lipid nanoparticles and injected into muscle.
In mice, the researchers compared intravenous, subcutaneous, and intramuscular delivery. Intravenous injection failed to produce detectable expression. Intramuscular injection worked best and kept reporter activity going for at least four weeks. Expression stayed confined to the injected hindlimb muscles, with no detectable leakage into major organs such as the liver or spleen.
Once produced in muscle, pro-ANP entered the bloodstream. The heart then converted it into active ANP through a protease called corin, which the team found was strongly enriched in the heart, especially in cardiomyocytes.
Cardioprotective factor pro-ANP expression was insufficient in adult hearts after MI. (CREDIT: Science)
“This technology gives us a more efficient way to help the body make what it needs, when it needs it,” Huang said. “A single dose can create a sustained effect, and that’s something we simply couldn’t achieve with older approaches.”
Better pumping, less scarring
In a mouse model of acute heart attack, animals received the injection on the same day as left anterior descending artery ligation. By day 28, treated hearts performed far better than controls. Left ventricular ejection fraction reached 40% in the treated group, compared with about 20% in mice given phosphate-buffered saline or control RNA nanoparticles.
The treated mice also had thicker ventricular walls, less chamber dilation, smaller infarcts, and less fibrosis. Those gains appeared in both female and male mice. A single dose of conventional nonreplicating Nppa mRNA did not produce the same cardioprotective effect, which underscored the value of the self-amplifying platform.
The team also tested the therapy under tougher conditions. It improved outcomes in aged mice, in an atherosclerosis model using Apoe knockout mice on a Western diet, in a metabolic syndrome model designed to mimic type 2 diabetes, and in an ischemia-reperfusion model that reflects clinical revascularization.
Delayed treatment still helped, though not as much. When the injection was given seven days after heart attack, ejection fraction improved from about 25% before treatment to about 35% to 40%, and scar area fell. But strain analyses did not show significant recovery of left ventricular strain abnormalities, suggesting some long-term risk remained.
One sentence stands out here: earlier treatment worked better.
Immunofluorescence staining of pro-ANP (yellow) in hearts from sham-operated and MI mice (α-actinin, magenta, CMs) on day 3 after MI. Nuclei were counterstained with 4′,6-diamidino-2-phenylindole (DAPI) (cyan). (CREDIT: Science) What the cells were doing differently
Single-nucleus RNA sequencing of more than 21,000 nuclei from mouse heart tissue suggested the therapy reshaped the cardiac environment rather than acting on one cell type alone. It appeared to preserve cardiomyocytes and endothelial cells, limit fibroblast expansion, and shift signaling in Npr1-positive cells toward a more reparative state.
The treated hearts showed stronger cGMP-PKG pathway activity, increased markers linked to cardiomyocyte proliferation, and reduced numbers of periostin-positive fibroblasts associated with fibrosis. The researchers also found lower expression of several profibrotic ligands in the treated group.
“Our goal is to protect the heart right when it’s most vulnerable,” Huang said. “If we can ease that early stress and support repair, we may be able to change the trajectory of recovery for patients.”
The road to patients is still long
The work involved collaborators from Texas A&M University, Columbia University, and the University of Oxford. In pigs, a single injection after ischemia-reperfusion injury raised ANP levels, improved ejection fraction, normalized wall thickness, and reduced fibrosis by day 28.
Still, this is not a ready-to-use therapy. The study was done in animals, not people. The injection caused transient weight loss in mice during the first week, and inflammatory cytokines rose sharply in muscle tissue within 24 hours, though systemic increases were more limited. The authors also note that innate immune responses to saRNA will need careful safety testing before any clinical translation.
Practical implications of the research
If the approach holds up in future studies, it could offer a simpler way to deliver heart-protective treatment after a heart attack without injecting the heart itself.
That matters because standard intramuscular delivery is easier to administer, less invasive, and may fit real-world care better than procedures that require direct cardiac access.
For now, the finding is best seen as a promising animal study that points toward a more practical form of regenerative heart therapy, not a treatment ready for patients.
Research findings are available online in the journal Science.
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