Abstract
Prolonged space missions expose astronauts to microgravity and cosmic radiation, leading to persistent vascular dysfunction driven by oxidative stress, cardiac deconditioning, and reduced physical activity. Current therapies are limited by adverse effects such as hypertension, hyperkalemia, and poor bioavailability, with no effective countermeasures targeting oxidative and endothelial-specific damage. Here, we present a multifunctional zein nanocage-based therapeutic formulation (ZNT) that encapsulates a remedial cocktail designed to mitigate oxidative stress and protect cardiovascular health under simulated microgravity conditions. In vitro studies on endothelial cells have revealed that microgravity induces reactive oxygen species generation, mitochondrial membrane depolarization, oxidative DNA damage, and apoptosis. These changes were accompanied by elevated nitric oxide production and aberrant expression of angiogenesis-related genes, including VEGFA, HIF-1α, eNOS, iNOS, FGF-2, and ANG1. Treatment with ZNT restored redox balance, preserved mitochondrial integrity, prevented DNA damage and apoptosis, and normalized angiogenic gene expression. These protective effects were further validated in vivo using zebrafish larvae and chick embryo models. By addressing both oxidative stress and pathological angiogenesis, ZNT emerges as a promising nanotherapeutic strategy to safeguard cardiovascular function during and after spaceflight, potentially filling a critical gap in astronaut healthcare.