Bioinspired Artificial Bioenergetic Organelles: Design Principles, Nanofabrication and Therapeutic Translation

Disruptions in cellular energy metabolism have emerged as central contributors to a broad spectrum of human diseases. While conventional therapeutic strategies can alleviate symptoms, they typically target downstream disease manifestations and often fail to address the underlying energetic dysregulation fueling disease progression. Bioenergetic organelles-engineered from mitochondria and thylakoids-represent a transformative approach by restoring cellular energy homeostasis. Functioning as autonomous metabolic modules, they generate ATP, reductive equivalents, and oxygen in situ, while concurrently modulating redox balance, oxygen tension, and immune-metabolic signaling to restore cellular homeostasis. Recent preclinical evidence highlights their therapeutic versatility, including alleviating tumor hypoxia, restoring bioenergetic function in myocardial and neuronal tissues, reducing inflammatory damage, and normalizing immune cell metabolism. Unlike nanocarriers that primarily serve as delivery vehicles, these bioenergetic organelles actively remodel pathological microenvironments by integrating metabolic restoration with multi-targeted therapeutic actions. This review outlines the design principles, mechanistic basis, and disease-specific applications of artificial bioenergetic organelles, while also addressing key translational challenges such as targeted delivery, immunocompatibility, functional longevity, critical considerations regarding biological safety, and the long-term metabolic fate of these constructs. Positioned at the convergence of bioenergetics, nanotherapeutics, and synthetic biology, these biomimetic systems offer a flexible platform for redefining disease intervention through precise metabolic regulation.