Integrating delivery systems and microenvironmental cues to accelerate clinical translation of cardiac reprogramming

Direct cardiac reprogramming, which converts cardiac fibroblasts into functional cardiomyocytes, has emerged as a promising regenerative strategy for heart failure. Preclinical studies have demonstrated its potential to mitigate adverse remodeling; however, critical challenges remain in delivery precision, reprogramming efficiency, and scalability for clinical translation. Here, we review innovations in delivery systems and microenvironmental engineering aimed at overcoming these barriers. Integration-free viral vectors (e.g. Sendai virus and adeno-associated virus 5) and non-viral platforms (e.g. nanoparticles and modified ribonucleic acid) have shown improved targeting of cardiac fibroblasts and enabled transient reprogramming. In parallel, microenvironmental modulation-such as immune regulation, biomechanical tuning of substrate stiffness, and the use of 3D-bioprinted matrices-has enhanced the survival and functionality of reprogrammed cells. Recent studies emphasize the need to balance genomic safety with delivery efficiency. While viral systems can achieve sustained factor expression, non-viral approaches minimize integration-associated risks. Large-animal models have further demonstrated the role of immune modulation and tissue-specific hydrogels in improving therapeutic retention. Advances in pericardial delivery systems and optimized manufacturing protocols now pave the way for future clinical translation. Nonetheless, unresolved issues-such as the long-term genomic stability of reprogrammed human cells and immune compatibility-still warrant rigorous investigation. By integrating targeted delivery, microenvironmental engineering, and scalable production, direct reprogramming strategies could redefine heart failure therapy. Collaborative efforts to address residual scientific and technical hurdles will determine their potential to benefit the 64 million patients affected globally.