Macrophage-mimetic photothermal nanotherapeutics regulate mitochondrial homeostasis and inflammatory cascades in lung ischemia-reperfusion injury.

Pulmonary ischemia-reperfusion injury is a major cause of acute lung injury and primary graft dysfunction after lung transplantation, with few effective treatments available. In this study, we develop a macrophage-membrane-coated mesoporous polydopamine nanoparticle system loaded with ginsenoside Rg3 (Rg3@PACVs) and activated by near-infrared irradiation. This design enables precise targeting of injured lung tissue via chemokine-receptor- and integrin-mediated pathways, while allowing controllable, on-demand drug release. In vitro hypoxia-reoxygenation models and a rat pulmonary ischemia-reperfusion model demonstrate that Rg3@PACVs with mild photothermal therapy reduce reactive oxygen species accumulation, suppress inflammatory cytokines, preserve mitochondrial structure and tricarboxylic acid cycle metabolism, and alleviate tissue injury. The approach combines targeted delivery, multimodal protection against oxidative and inflammatory damage, and mitochondrial restoration. These findings suggest a promising therapeutic strategy for mitigating lung ischemia-reperfusion injury and potentially for other inflammation- and oxidative-stress-driven pulmonary diseases.