Organelle-targeted nanomedicine for metabolic reprogramming in regenerative medicine

Cellular metabolism is a central determinant of regenerative outcomes, governing survival, proliferation, differentiation, and paracrine signaling of stem, progenitor, parenchymal, and immune cells in injured tissues. Organelle-targeted nanomedicine has emerged as a powerful strategy to reprogram metabolism with subcellular precision by directing therapeutic cargos to mitochondria, endoplasmic reticulum, lysosomes, peroxisomes, the nucleus, or the Golgi apparatus. This review first outlines organelle-centric control of metabolic flux, proteostasis, redox balance, and epigenetic state in key regenerative cell populations and tissues. It then discusses design principles for organelle-targeting nanoplatforms, including mitochondria-penetrating cations and peptides, ER- and lysosome-directed ligands, peroxisomal targeting signals, nuclear localization strategies, and multi-organelle and stimuli-responsive architectures. We next highlight preclinical applications in skeletal, cardiac, neural, cutaneous, hepatic, and metabolic organ regeneration, emphasizing how organelle-focused interventions reshape immunometabolism and the regenerative microenvironment. Translational considerations, encompassing biodistribution, safety, manufacturability, regulatory classification, and ethical issues, are critically examined, alongside emerging exosome-based and hybrid cell-free approaches. Finally, we propose future directions that integrate organelle-resolved multi-omics, adaptive nanomedicine, and gene and cell engineering to achieve durable, clinically relevant metabolic reprogramming. Collectively, organelle-targeted nanomedicine offers a versatile framework to convert maladaptive repair into true regeneration.