Emerging advances in gene and cell therapy for heart failure: a systematic review

Abstract Heart failure (HF) remains a major global health burden, and current therapies slow disease progression but rarely reverse myocardial dysfunction. Gene and cell therapies have emerged as innovative strategies capable of directly modifying molecular pathways and promoting cardiac repair. Recent progress in vector engineering, CRISPR-based genome editing, and delivery systems has strengthened the feasibility of targeting impaired calcium handling, β-adrenergic signaling, angiogenesis, and cytoprotective mechanisms. In parallel, stem-cell-derived cardiomyocytes and progenitor cells demonstrate regenerative and paracrine benefits, although challenges related to immune responses, cytokine- and chemokine-mediated signaling, cell survival, and clinical scalability persist. Despite encouraging preclinical and early clinical findings, translation remains limited by immunogenicity, inadequate transgene expression, and cost and access barriers. This systematic review synthesizes emerging trends and ongoing clinical trials, highlights factors underlying variable outcomes, and discusses future directions needed to advance these therapies toward routine clinical application.