# Intratracheal Delivery of a Phospholamban Decoy Peptide Attenuates Cardiac Damage Following Myocardial Infarction

## TL;DR

A new method of delivering a heart-protecting peptide via the lungs shows promise in preventing heart damage after a heart attack.

## Contribution

A novel lung-to-heart delivery system using a CPP-conjugated decoy peptide to treat heart failure is introduced.

## Key findings

- Intratracheal delivery of dNP2-SE leads to efficient heart accumulation and peak concentration at 3 hours post-injection.
- dNP2-SE prevents PLN dephosphorylation and disrupts PP1-PLN interaction, improving heart function after myocardial infarction.
- The CPP-conjugated peptide significantly reduces morphological and functional deterioration of the heart.

## Abstract

Heart failure (HF) remains a major cause of mortality worldwide. While novel approaches, including gene and cell therapies, show promise, efficient delivery methods for such biologics to the heart are critically needed. One emerging strategy is lung-to-heart delivery using nanoparticle (NP)-encapsulated biologics. This study examines the efficiency of delivering a therapeutic peptide conjugated to a cell-penetrating peptide (CPP) to the heart via the lung-to-heart route through intratracheal (IT) injection in mice. The CPP, a tandem repeat of NP2 (dNP2) derived from the human novel LZAP-binding protein (NLBP), facilitates intracellular delivery of the therapeutic payload. The therapeutic peptide, SE, is a decoy peptide designed to inhibit protein phosphatase 1 (PP1)-mediated dephosphorylation of phospholamban (PLN). Our results demonstrated that IT injection of dNP2-SE facilitated efficient delivery to the heart, with peak accumulation at 3 h post-injection. The administration of dNP2-SE significantly ameliorated morphological and functional deterioration of the heart under myocardial infarction. At the molecular level, dNP2-SE effectively prevented PLN dephosphorylation in the heart. Immunoprecipitation experiments further revealed that dNP2-SE binds strongly to PP1 and disrupts its interaction with PLN. Collectively, our findings suggest that lung-to-heart delivery of a CPP-conjugated therapeutic peptide, dNP2-SE, represents a promising approach for the treatment of HF.