Inhalable ROS‐Responsive Nanospray Activates PPAR‐γ to Restore Macrophage Mitochondrial Homeostasis and Attenuate Radiation‐Induced Lung Injury

ABSTRACT 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.