Continuous loss of cardiomyocytes (CMs) is one of the fundamental characteristics of many heart diseases, which eventually can lead to heart failure. Due to the limited proliferation ability of human adult CMs, treatment efficacy has been limited in terms of fully repairing damaged hearts. It has been shown that cell lineage conversion can be achieved by using cell reprogramming approaches, including human induced pluripotent stem cells (hiPSCs), providing a promising therapeutic for regenerative heart medicine. Recent studies using advanced cellular reprogramming-based techniques have also contributed some new strategies for regenerative heart repair. In this review, hiPSC-derived cell therapeutic methods are introduced, and the clinical setting challenges (maturation, engraftment, immune response, scalability, and tumorigenicity), with potential solutions, are discussed. Inspired by the iPSC reprogramming, the approaches of direct cell lineage conversion are merging, such as induced cardiomyocyte-like cells (iCMs) and induced cardiac progenitor cells (iCPCs) derived from fibroblasts, without induction of pluripotency. The studies of cellular and molecular pathways also reveal that epigenetic resetting is the essential mechanism of reprogramming and lineage conversion. Therefore, CRISPR techniques that can be repurposed for genomic or epigenetic editing become attractive approaches for cellular reprogramming. In addition, viral and non-viral delivery strategies that are utilized to achieve CM reprogramming will be introduced, and the therapeutic effects of iCMs or iCPCs on myocardial infarction will be compared. After the improvement of reprogramming efficiency by developing new techniques, reprogrammed iCPCs or iCMs will provide an alternative to hiPSC-based approaches for regenerative heart therapies, heart disease modeling, and new drug screening.

Cardiovascular diseases resulting from myocardial infarction (MI) remain a leading cause of death worldwide, imposing a substantial burden on global health systems. Current MI treatments, primarily pharmacological and surgical, do not regenerate lost myocardium, leaving patients at high risk for heart failure. Engineered heart tissue (EHT) offers a promising solution for MI and related cardiac conditions by replenishing myocardial loss. However, challenges like immune rejection, inadequate vascularization, limited mechanical strength, and incomplete tissue maturation hinder clinical application. The discovery of human-induced pluripotent stem cells (hiPSCs) has transformed the EHT field, enabling new bioengineering innovations. This review explores recent advancements and future directions in hiPSC-derived EHTs, focusing on innovative materials and fabrication methods like bioprinting and decellularization, and assessing their therapeutic potential through preclinical and clinical studies. Achieving functional integration of EHTs in the heart remains challenging due to the need for synchronized contraction, sufficient vascularization, and mechanical compatibility. Solutions such as genome editing, personalized medicine, and AI technologies offer promising strategies to address these translational barriers. Beyond MI, EHTs also show potential in treating ischemic cardiomyopathy, heart valve engineering, and drug screening, underscoring their promise in cardiovascular regenerative medicine.

Myocardial infarction-induced cardiovascular diseases remain a leading cause of mortality worldwide. Excessive post-infarct fibrosis contributes to adverse cardiac remodeling and the progression to heart failure. In vivo reprogramming strategies offer a promising avenue for heart regeneration by directly converting resident fibroblasts into cardiomyocytes through enforced expression of cardiogenic genes. This approach circumvents the need for invasive biopsies, cell expansion, induction of pluripotency, or autologous transplantation. Despite these advantages, key challenges persist, including low reprogramming efficiency and limited cellular targeting specificity. A critical factor for effective anti-fibrotic therapy is the precise and efficient delivery of reprogramming effectors specifically to fibrotic fibroblasts, while minimizing off-target effects on non-fibroblast cardiac cells and fibroblasts in non-cardiac tissues. In this review, we discuss the cellular and molecular mechanisms underlying in vivo cardiac reprogramming, with a focus on fibroblast heterogeneity, key transcriptional drivers, and relevant intercellular interactions. We also examine current advances in fibroblast-specific delivery systems employing both viral and non-viral vectors for the administration of lineage-reprogramming factors such as cDNA overexpressions or microRNAs. Finally, we underscore innovative strategies that hold promise for enhancing the precision and efficacy of cellular reprogramming, ultimately fostering translational development and paving the way for rigorous preclinical assessment.

Cardiovascular diseases remain a leading cause of hospitalization affecting approximately 38 million people worldwide. While pharmacological and revascularization techniques can improve the patient’s survival and quality of life, they cannot help reversing myocardial infarction injury and heart failure. Direct reprogramming of somatic cells to cardiomyocyte and cardiac progenitor cells offers a new approach to cellular reprogramming and paves the way for translational regenerative medicine. Direct reprogramming can bypass the pluripotent stage with the potential advantage of non-immunogenic cell products, reduced carcinogenic risk, and no requirement for embryonic tissue. The process of directly reprogramming cardiac cells was first achieved through the overexpression of transcription factors such as GATA4, MEF2C, and TBX5. However, over the past decade, significant work has been focused on enhancing direct reprogramming using a mixture of transcription factors, microRNAs, and small molecules to achieve cardiac cell fate. This review discusses the evolution of direct reprogramming, recent progress in achieving efficient cardiac cell fate conversion, and describes the reprogramming mechanisms at a molecular level. We also explore various viral and non-viral delivery methods currently being used to aid in the delivery of reprogramming factors to improve efficiency. However, further studies will be needed to overcome molecular and epigenetic barriers to successfully achieve translational cardiac regenerative therapeutics.

The current standard of care for posterior segment eye diseases, such as age-related macular degeneration and diabetic macular edema, is frequent intravitreal injections or sustained-release drug implants. Drug implants have side effects due to the burst release of the drugs, and their release cannot be easily controlled after implantation. Present study attempts to develop a dosage-controllable drug delivery implant which consists of a nanoporous biodegradable PLGA capsule and light-activated liposomes. Controllable drug release from the implant was achieved by using pulsed near-infrared (NIR) laser both in vitro and in vivo. The in vitro drug release kinetics from two different initial dose implants, 1000 μg and 500 μg, was analyzed by fitting zero order and first order kinetics, as well as the Korsmeyer-Peppas and Higuchi models. The 1000 μg and 500 μg implants fit the first-order and zero-order kinetics model, respectively, the best. The multiple drug releases in the vitreous was determined by in vivo fluorimeter, which was consistent with the in vitro data. The dose released was also clinically relevant. Histology and optical and ultrasound imaging data showed no abnormality in the eyes received implant treatment suggesting that the drug delivery system was safe to the retina. This on-demand dose-controllable drug delivery system could be potentially used for long-term posterior eye disease treatment.