Radiation-induced lung injury (RILI) is a major complication of nuclear radiation exposure and thoracic radiotherapy, driven in part by a vicious cycle of oxidative stress and mitochondrial dysfunction. Peroxisome proliferator-activated receptor gamma (PPAR-γ), a key regulator of mitochondrial homeostasis and inflammatory resolution, therefore represents a potential therapeutic target, yet multi-omics analyses revealed that this immunometabolic checkpoint remains functionally constrained in irradiated macrophages. To reactivate this pathway, we developed an inhalable, ROS-responsive nanospray (HANP) by loading nicotinamide adenine dinucleotide (NAD+) and astaxanthin (ASX) into a hollow mesoporous polydopamine (HMPDA) shell. Excess ROS in microenvironment triggers oxidative degradation of the HMPDA shell, enabling intracellular release of NAD+ and ASX. Mechanistically, NAD+ promotes SIRT1-mediated deacetylation of PPAR-γ, whereas ASX serves as an activating ligand, thereby cooperatively restoring PPAR-γ signaling. This response re-establishes macrophage mitochondrial homeostasis by coordinating mitochondrial biogenesis and mitophagy, which subsequently promotes a shift toward a reparative macrophage phenotype. In murine models of focal thoracic irradiation and lethal whole-body irradiation, HANP markedly attenuated lung injury and improved survival. Collectively, these findings identify macrophage PPAR-γ as a therapeutically actionable redox-immunometabolic regulator and support inhaled dual-activation of this pathway as a promising strategy for protection against RILI in both clinical and emergency settings.
