# Next-Generation Metabolic Reprogramming in iPSC-Derived Cardiomyocytes: CRISPR-EV Synergy for Precision Cardiac Regeneration

## TL;DR

This paper explores combining CRISPR and extracellular vesicles to improve the metabolic maturity of heart cells derived from stem cells for better cardiac regeneration.

## Contribution

The novel approach integrates CRISPR-based metabolic engineering with EV-mediated modulation to achieve durable metabolic maturation in iPSC-derived cardiomyocytes.

## Key findings

- CRISPR techniques targeting PGC-1α, TFAM, and PPARs enhance mitochondrial networks and respiratory capacity in iPSC-CMs.
- Engineered EVs delivering miRNAs and metabolic enzymes optimize bioenergetic function and reduce oxidative stress.
- The synergy of CRISPR and EVs offers a precision framework for cardiac maturation and regenerative therapy.

## Abstract

Cardiovascular disease remains the leading global cause of mortality, largely due to the limited regenerative capacity of adult human myocardium. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) offer a scalable platform for cardiac repair and disease modeling; however, their persistent metabolic immaturity—characterized by reliance on glycolysis, reduced oxidative phosphorylation (OXPHOS), and structurally underdeveloped mitochondria—limits functional integration and long-term therapeutic efficacy. Recent advances indicate that targeted metabolic reprogramming can enhance mitochondrial biogenesis, increase ATP production, and improve stress resilience in iPSC-CMs. This review examines the complementary integration of CRISPR-based metabolic engineering and extracellular vesicle (EV)-mediated metabolic modulation as a systems-level strategy for cardiac maturation. We discuss CRISPR activation, interference, and epigenome-editing approaches targeting regulators such as PGC-1α, TFAM, and PPARs to promote stable enhancement of mitochondrial networks and respiratory capacity. In parallel, engineered EVs delivering miRNAs, metabolic enzymes, and redox modulators provide non-genomic mechanisms to optimize bioenergetic function and mitigate oxidative stress. By synthesizing mechanistic insights, quantitative bioenergetic metrics, and translational considerations, we propose CRISPR-EV synergy as a precision framework for durable metabolic maturation of iPSC-CMs, with implications for regenerative therapy, pharmacologic screening, and myocardial repair.